Lysyl oxidase-like 2 inhibitors and uses thereof

ABSTRACT

Described herein are compounds that are LOXL2 inhibitors, methods of making such compounds, pharmaceutical compositions and medicaments comprising such compounds, and methods of using such compounds in the treatment of conditions, diseases, or disorders associated with LOXL2 activity.

RELATED APPLICATIONS

This application is filed pursuant to 35 U.S.C. § 371 as a United StatesNational Phase Application of International Application No.PCT/US2016/020731 entitled “LYSYL OXIDASE-LIKE 2 INHIBITORS AND USESTHEREOF” filed Mar. 3, 2016, which claims the benefit of U.S.Provisional Patent Application No. 62/129,531 filed on Mar. 6, 2015,each of which is incorporated herein by reference in its entirety.

FIELD OF THE INVENTION

Described herein are compounds that are lysyl oxidase-like 2 (LOXL2)inhibitors, methods of making such compounds, pharmaceuticalcompositions and medicaments comprising such compounds, and methods ofusing such compounds in the treatment of conditions, diseases, ordisorders associated with LOXL2 activity.

BACKGROUND OF THE INVENTION

Lysyl oxidase like-2 (LOXL2) is an amine oxidase enzyme that catalyzescrosslinking of extracellular matrix proteins. LOXL2 is also involved inintracellular processes such as mediating epithelial-to-mesenchymaltransition of cells. LOXL2 signaling is implicated in, for example, infibrotic diseases and cancer.

SUMMARY OF THE INVENTION

In one aspect, described herein are LOXL2 inhibitors and uses thereof.In some embodiments, the LOXL2 inhibitors described herein have thestructure of Formula (I), or a pharmaceutically acceptable salt thereof.

In one aspect, described herein is a method of treating a disease orcondition in a mammal that would benefit from the inhibition orreduction of Lysyl oxidase like-2 (LOXL2) activity comprisingadministering a substituted pyridinylmethylamine compound, or apharmaceutically acceptable salt, or solvate thereof, to the mammal inneed thereof. In some embodiments, the disease or condition is fibrosisor cancer. In some embodiments, the substituted pyridinylmethylaminecompound, or a pharmaceutically acceptable salt, or solvate thereof, isa Lysyl oxidase like-2 (LOXL2) inhibitor. In some embodiments, thesubstituted pyridinylmethylamine compound is a substitutedpyridin-4-ylmethylamine compound.

In another aspect, described herein is a method of treating fibrosis ina mammal comprising administering a substituted pyridinylmethylaminecompound, or a pharmaceutically acceptable salt, or solvate thereof, tothe mammal in need thereof. In some embodiments, the fibrosis compriseslung fibrosis, liver fibrosis, kidney fibrosis, cardiac fibrosis,peritoneal fibrosis, ocular fibrosis or cutaneous fibrosis. In someembodiments, the fibrosis is myelofibrosis. In some embodiments, thesubstituted pyridinylmethylamine compound, or a pharmaceuticallyacceptable salt, or solvate thereof, is a Lysyl oxidase like-2 (LOXL2)inhibitor. In some embodiments, the substituted pyridinylmethylaminecompound is a substituted pyridin-4-ylmethylamine compound.

In some embodiments, the substituted pyridinylmethylamine compound, or apharmaceutically acceptable salt, or solvate thereof, has the structureof Formula (I), or a pharmaceutically acceptable salt, or solvatethereof:

-   -   wherein,    -   each R¹ is independently H, D, or F;    -   R^(A) is H, D, halogen, —CN, —OR⁵, —SR⁵, —S(═O)R⁴, —S(═O)₂R⁴,        —S(═O)₂N(R⁵)₂, —NR²S(═O)₂R⁴, —C(═O)R⁴, —OC(═O)R⁴, —CO₂R⁵,        —OCO₂R⁵, —N(R⁵)₂, —OC(═O)N(R⁵)₂, —NR²C(═O)R⁴, —NR²C(═O)OR⁵,        —CH₃, —CH₂F, —CHF₂, substituted or unsubstituted C₂-C₆alkyl,        C₁-C₆deuteroalkyl, C₁-C₆heteroalkyl, substituted or        unsubstituted C₃-C₁₀cycloalkyl, substituted or unsubstituted        C₂-C₁₀heterocycloalkyl, substituted or unsubstituted aryl, or        substituted or unsubstituted heteroaryl;    -   R^(B) is H, D, halogen, —CN, —OR⁵, —SR⁵, —S(═O)R⁴, —S(═O)₂R⁴,        —S(═O)₂N(R⁵)₂, —NR²S(═O)₂R⁴, —C(═O)R⁴, —OC(═O)R⁴, —CO₂R⁵,        —OCO₂R⁵, —N(R⁵)₂, —OC(═O)N(R⁵)₂, —NR²C(═O)R⁴, —NR²C(═O)OR⁵,        C₁-C₆alkyl, —CH₂F, —CHF₂, C₂-C₆fluoroalkyl, C₁-C₆deuteroalkyl,        C₁-C₆heteroalkyl, substituted or unsubstituted C₃-C₁₀cycloalkyl,        substituted or unsubstituted C₂-C₁₀heterocycloalkyl, substituted        or unsubstituted aryl, or substituted or unsubstituted        heteroaryl;    -   or R^(B) is

-   -   -   L¹ is absent, X¹, X¹—C₁-C₆alkylene, or C₁-C₆alkylene;        -   X¹ is —O—, —S—, —S(═O)—, —S(═O)₂—, —C(═O)—, —C(═O)O—,            —C(═O)NR²—, —NR²C(═O)—, or —NR²—;        -   R² is H, substituted or unsubstituted C₁-C₆alkyl,            C₁-C₆fluoroalkyl, or C₁-C₆deuteroalkyl;        -   each R³ is independently H, D, halogen, —CN, —OR⁵, —SR⁵,            —S(═O)R⁴, —S(═O)₂R⁴, —S(═O)₂N(R⁵)₂, —NR²S(═O)₂R⁴, —C(═O)R⁴,            —OC(═O)R⁴, —CO₂R⁵, —OCO₂R⁴, —N(R⁵)₂, —OC(═O)N(R⁵)₂,            —NR²C(═O)R⁴, —NR²C(═O)OR⁴, C₁-C₆alkyl, C₁-C₆fluoroalkyl,            C₁-C₆deuteroalkyl, C₁-C₆heteroalkyl, substituted or            unsubstituted C₃-C₁₀cycloalkyl, substituted or unsubstituted            C₂-C₁₀heterocycloalkyl, substituted or unsubstituted aryl,            or substituted or unsubstituted heteroaryl;            -   m is 0, 1, or 2;        -   each R⁴ is independently selected from C₁-C₆alkyl,            C₁-C₆fluoroalkyl, C₁-C₆deuteroalkyl, C₁-C₆heteroalkyl,            substituted or unsubstituted C₃-C₁₀cycloalkyl, substituted            or unsubstituted C₂-C₁₀heterocycloalkyl, substituted or            unsubstituted aryl, and substituted or unsubstituted            heteroaryl;        -   each R⁵ is independently selected from H, C₁-C₆alkyl,            C₁-C₆fluoroalkyl, C₁-C₆deuteroalkyl, C₁-C₆heteroalkyl,            substituted or unsubstituted C₃-C₁₀cycloalkyl, substituted            or unsubstituted C₂-C₁₀heterocycloalkyl, substituted or            unsubstituted aryl, substituted or unsubstituted heteroaryl,            —C₁-C₄alkylene-(substituted or unsubstituted            C₃-C₈cycloalkyl), substituted or unsubstituted            C₂-C₈heterocycloalkyl, —C₁-C₄alkylene-(substituted or            unsubstituted C₂-C₈heterocycloalkyl), substituted or            unsubstituted aryl, —C₁-C₄alkylene-(substituted or            unsubstituted aryl), substituted or unsubstituted            heteroaryl, and —C₁-C₄alkylene-(substituted or unsubstituted            heteroaryl); or two R⁵ on the same N atom are taken together            with the N atom to which they are attached to a substituted            or unsubstituted N-containing heterocycle;        -   Ring A is monocyclic carbocycle, bicyclic carbocycle,            monocyclic heterocycle, or bicyclic heterocycle;        -   L² is absent, —X²—, or —C₁-C₆alkylene-X²—;            -   X² is —O—, —S—, —S(═O)—, —S(═O)₂—, —S(═O)₂NR⁶—, —C(═O)—,                —C(═O)₂—, —C(═O)NR⁶—, —NR⁶C(═O)—, —NR⁶S(═O)₂—, or —NR⁶—;            -   R⁶ is H, C₁-C₆alkyl, C₁-C₆fluoroalkyl, or                C₁-C₆deuteroalkyl;            -   Q is H, substituted or unsubstituted C₁-C₆alkyl,                substituted or unsubstituted C₁-C₆fluoroalkyl,                substituted or unsubstituted C₁-C₆heteroalkyl,                substituted or unsubstituted C₃-C₈cycloalkyl,                —C₁-C₄alkylene-(substituted or unsubstituted                C₃-C₈cycloalkyl), substituted or unsubstituted                C₂-C₈heterocycloalkyl, —C₁-C₄alkylene-(substituted or                unsubstituted C₂-C₈heterocycloalkyl), substituted or                unsubstituted aryl, —C₁-C₄alkylene-(substituted or                unsubstituted aryl), substituted or unsubstituted                heteroaryl, or —C₁-C₄alkylene-(substituted or                unsubstituted heteroaryl); wherein if Q is substituted                then Q is substituted with one or more R⁸;            -   or Q and R⁶ are taken together with the N atom to which                they are attached to form ring B, wherein ring B is a                substituted or unsubstituted N-containing heterocycle,                wherein if ring B is substituted then ring B is                substituted with 1-3 R⁸;            -   each R⁸ is independently D, halogen, CN, —OR⁵, —SR⁵,                —S(═O)R⁴, —S(═O)₂R⁴, —S(═O)₂N(R⁵)₂, NR⁵S(═O)₂R⁴,                C(═O)R⁴, OC(═O)R⁴, CO₂R⁵, OCO₂R⁴, N(R⁴)₂, OC(═O)N(R⁵)₂,                —NHC(═O)R⁴, —NHC(═O)OR⁴, C₁-C₆alkyl, C₁-C₆fluoroalkyl,                C₁-C₆deuteroalkyl, C₁-C₆heteroalkyl, substituted or                unsubstituted C₃-C₁₀cycloalkyl, substituted or                unsubstituted C₂-C₁₀heterocycloalkyl, substituted or                unsubstituted aryl, or substituted or unsubstituted                heteroaryl;            -   or two R⁸ groups attached to the same carbon atom are                taken together with carbon atom to which they are                attached to form either a substituted or unsubstituted                carbocycle or substituted or unsubstituted heterocycle.

For any and all of the embodiments, substituents are selected from amonga subset of the listed alternatives. For example, in some embodiments,each R¹ is independently H, D, or F. In some other embodiments, each R¹is independently H, or F. In other embodiments, each R¹ is H. In someembodiments, each R¹ is D. In some embodiments, each R¹ is F.

In some embodiments, R^(A) is H, D, F, Cl, Br, —CN, —OR⁵, —SR⁵,—S(═O)R⁴, —S(═O)₂R⁴, —S(═O)₂N(R⁵)₂, —NR²S(═O)₂R⁴, —CO₂R⁵, —N(R⁵)₂,—NR²C(═O)R⁴, C₁-C₆alkyl, substituted or unsubstituted C₃-C₆cycloalkyl,substituted or unsubstituted C₂-C₆heterocycloalkyl, substituted orunsubstituted phenyl, or substituted or unsubstituted monocyclicheteroaryl. In some embodiments, R^(A) is H, D, F, Cl, Br, —CN, —OR⁵,—CO₂R⁵, —N(R⁵)₂, —NR²C(═O)R⁴, —CH₃, —CH₂CH₃, —CH(CH₃)₂, —C(CH₃)₃,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, substituted orunsubstituted monocyclic C₂-C₆heterocycloalkyl, substituted orunsubstituted phenyl, or substituted or unsubstituted monocyclicheteroaryl. In some embodiments, R^(A) is H.

In some embodiments, R¹ is H.

In some embodiments, the compound has the following structure of Formula(II):

In some embodiments, R^(B) is H, D, F, Cl, Br, I, —CN, —OR⁵, —SR⁵,—S(═O)R⁴, —S(═O)₂R⁴, —S(═O)₂N(R⁵)₂, —NR²S(═O)₂R⁴, —C(═O)R⁴, —OC(═O)R⁴,—CO₂R⁵, —N(R⁵)₂, —NR²C(═O)R⁴, C₁-C₆alkyl, C₁-C₆fluoroalkyl,C₁-C₆deuteroalkyl, C₁-C₆heteroalkyl, substituted or unsubstitutedC₃-C₆cycloalkyl, substituted or unsubstituted monocyclicC₂-C₆heterocycloalkyl, substituted or unsubstituted phenyl, orsubstituted or unsubstituted monocyclic heteroaryl.

In some embodiments, R^(B) is H, D, F, Cl, —CN, —OR⁵, —SR⁵,—NR²S(═O)₂R⁴, —CO₂R⁵, —N(R⁵)₂, —NR²C(═O)R⁴, C₁-C₆alkyl,C₁-C₆fluoroalkyl, substituted or unsubstituted C₃-C₆cycloalkyl,substituted or unsubstituted monocyclic C₂-C₆heterocycloalkyl,substituted or unsubstituted phenyl, or substituted or unsubstitutedmonocyclic heteroaryl.

In some embodiments, or R^(B) is

In some embodiments, the compound has the following structure of Formula(III):

In some embodiments, each R¹ is H; L¹ is absent, X¹, orX¹—C₁-C₆alkylene.

In some embodiments, X¹ is —O—.

In some embodiments, L¹ is absent, —O—, or —O—CH₂—, —C(═O)—,—C(═O)NHCH₂—, —NHC(═O)—, —NHC(═O)CH₂—.

In some embodiments, the compound has the structure of Formula (IV), ora pharmaceutically acceptable salt thereof:

In some embodiments, L¹ is —O—, or —O—CH₂—.

In some embodiments, the compound has the structure of Formula (V), or apharmaceutically acceptable salt thereof:

In some embodiments, Ring A is monocyclic C₃-C₆carbocycle, bicyclicC₅-C₁₂carbocycle, monocyclic C₁-C₅heterocycle, bicyclicC₅-C₁₀heterocycle.

In some embodiments, Ring A is monocyclic C₃-C₆carbocycle, bicyclicC₉-C₁₀carbocycle, monocyclic C₁-C₅heterocycle, bicyclicC₆-C₉heterocycle. In some embodiments, Ring A is monocyclicC₃-C₆carbocycle. In some embodiments, Ring A is phenyl, cyclopropyl,cyclobutyl, cyclopentyl, or cyclohexyl. In some embodiments, Ring A isphenyl.

In some embodiments, Ring A is

In some embodiments, Ring A is

In some embodiments, Ring A is a bicyclic C₅-C₁₂carbocycle. In someembodiments, Ring A is a bicyclic C₅-C₁₂carbocycle that is a fusedC₅-C₁₂carbocycle, bridged C₅-C₁₂carbocycle, or spirocyclicC₅-C₁₂carbocycle.

In some embodiments, Ring A is bicyclic C₉-C₁₀carbocycle. In someembodiments, Ring A is naphthyl, indanyl, indenyl, ortetrahyodronaphthyl.

In some embodiments, Ring A is a monocyclic heterocycle containing 1-4 Natoms and 0 or 1 O or S atom, monocyclic heterocycle containing 0-4 Natoms and 1 O or S atoms, bicyclic heterocycle containing 1-4 N atomsand 0 or 1 O or S atoms, or bicyclic heterocycle containing 0-4 N atomsand 1 O or S atoms.

In some embodiments, Ring A is pyrrolidinyl, pyrrolidinonyl,tetrahydrofuranyl, tetrahydrofuranonyl, dihydrofuranonyl,dihydrofuranyl, tetrahydrothienyl, oxazolidinonyl, tetrahydropyranyl,dihydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl,thiomorpholinyl, piperazinyl, aziridinyl, azetidinyl, oxetanyl,thietanyl, homopiperidinyl, oxepanyl, thiepanyl, oxazepinyl, diazepinyl,thiazepinyl, 1,2,3,6-tetrahydropyridinyl, indolinyl, indolinonyl,1,2,3,4-tetrahydroquinolinyl, 1,2,3,4-tetrahydroisoquinolinyl,3,4-dihydro-2(1H)-quinolinonyl, furanyl, pyrrolyl, oxazolyl, thiazolyl,imidazolyl, pyrazolyl, triazolyl, tetrazolyl, isoxazolyl, isothiazolyl,oxadiazolyl, thiadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl,pyridazinyl, triazinyl, quinolinyl, isoquinolinyl, quinazolinyl,quinoxalinyl, naphthyridinyl, indolyl, indazolyl, benzoxazolyl,benzisoxazolyl, benzofuranyl, benzothienyl, benzothiazolyl,benzimidazolyl, purinyl, cinnolinyl, phthalazinyl, pteridinyl,pyridopyrimidinyl, pyrazolopyrimidinyl, or azaindolyl.

In some embodiments, Ring A is pyrrolidinyl, pyrrolidinonyl,piperidinyl, piperazinyl, indolinyl, indolinonyl,1,2,3,4-tetrahydroquinolinyl, 1,2,3,4-tetrahydroisoquinolinyl,3,4-dihydro-2(1H)-quinolinonyl, pyrrolyl, imidazolyl, pyrazolyl,pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, indolyl, indazolyl, orbenzimidazolyl.

In some embodiments, Ring A is

In some embodiments, Ring A is a bicyclic C₅-C₁₀heterocycle containing1-4 N atoms and 0 or 1 O or S atoms, or bicyclic heterocycle containing0-4 N atoms and 1 O or S atoms that is a fused bicyclicC₅-C₁₀heterocycle, bridged bicyclic C₅-C₁₀ heterocycle, or spirobicyclic C₅-C₁₀heterocycle.

In some embodiments, Ring A is

In some embodiments, L² is absent, —O—, —CH₂—O—, —C(═O)—, —C(═O)NR⁶—,—NR⁶C(═O)—, —NR⁶—, or —CH₂—C(═O)NR⁶—.

In some embodiments, Q is H, substituted or unsubstituted C₁-C₆alkyl,substituted or unsubstituted C₁-C₆fluoroalkyl, substituted orunsubstituted C₁-C₆heteroalkyl, substituted or unsubstitutedC₃-C₆cycloalkyl, —C₁-C₂alkylene-(substituted or unsubstitutedC₃-C₆cycloalkyl), substituted or unsubstituted C₂-C₈heterocycloalkyl,—C₁-C₂alkylene-(substituted or unsubstituted C₂-C₈heterocycloalkyl),substituted or unsubstituted phenyl, —C₁-C₂alkylene-(substituted orunsubstituted phenyl), substituted or unsubstituted heteroaryl, or—C₁-C₂alkylene-(substituted or unsubstituted heteroaryl); wherein if Qis substituted then Q is substituted with one or more R⁸; or Q and R⁶are taken together with the N atom to which they are attached to formring B, wherein ring B is a substituted or unsubstituted monocyclicN-containing heterocycle, or a substituted or unsubstituted bicyclicN-containing heterocycle, wherein if ring B is substituted then ring Bis substituted with 1-3 R⁸.

In some embodiments, Q is substituted or unsubstituted C₃-C₆cycloalkyl,—C₁-C₂alkylene-(substituted or unsubstituted C₃-C₆cycloalkyl),substituted or unsubstituted C₂-C₈heterocycloalkyl,—C₁-C₂alkylene-(substituted or unsubstituted C₂-C₈heterocycloalkyl),substituted or unsubstituted phenyl, —C₁-C₂alkylene-(substituted orunsubstituted phenyl), substituted or unsubstituted heteroaryl, or—C₁-C₂alkylene-(substituted or unsubstituted heteroaryl); wherein if Qis substituted then Q is substituted with one or more R⁸; or Q and R⁶are taken together with the N atom to which they are attached to formring B, wherein ring B is a substituted or unsubstituted monocyclicN-containing heterocycle, or a substituted or unsubstituted bicyclicN-containing heterocycle, wherein if ring B is substituted then ring Bis substituted with 1-3 R⁸.

In some embodiments, L² is —C(═O)NR⁶—, or —CH₂—C(═O)NR⁶—; Q is H,substituted or unsubstituted C₁-C₆alkyl, substituted or unsubstitutedC₁-C₆fluoroalkyl, substituted or unsubstituted C₁-C₆heteroalkyl,substituted or unsubstituted C₃-C₆cycloalkyl,—C₁-C₂alkylene-(substituted or unsubstituted C₃-C₆cycloalkyl),substituted or unsubstituted C₂-C₈heterocycloalkyl,—C₁-C₂alkylene-(substituted or unsubstituted C₂-C₈heterocycloalkyl),substituted or unsubstituted phenyl, —C₁-C₂alkylene-(substituted orunsubstituted phenyl), substituted or unsubstituted heteroaryl, or—C₁-C₂alkylene-(substituted or unsubstituted heteroaryl); wherein if Qis substituted then Q is substituted with one or more R⁸; or Q and R⁶are taken together with the N atom to which they are attached to formring B, wherein ring B is a substituted or unsubstituted monocyclicN-containing heterocycle, or a substituted or unsubstituted bicyclicN-containing heterocycle, wherein if ring B is substituted then ring Bis substituted with 1-3 R⁸.

In some embodiments, the compound described herein has the structure ofFormula (VI), or a pharmaceutically acceptable salt thereof:

In some embodiments, -L²-Q is —C(═O)NR⁶-Q; Q and R⁶ are taken togetherwith the N atom to which they are attached to form a ring B, whereinring B is a substituted or unsubstituted monocyclic N-containingheterocycle, or a substituted or unsubstituted bicyclic N-containingheterocycle, wherein if ring B is substituted then ring B is substitutedwith 1-3 R⁸.

In some embodiments, Q and R⁶ are taken together with the N atom towhich they are attached to form a ring B, wherein ring B is asubstituted or unsubstituted aziridinyl, substituted or unsubstitutedazetidinyl, substituted or unsubstituted pyrrolidinyl, substituted orunsubstituted pyrrolidinonyl, substituted or unsubstituted piperidinyl,substituted or unsubstituted piperidinonyl, substituted or unsubstitutedmorpholinyl, substituted or unsubstituted thiomorpholinyl, substitutedor unsubstituted piperazinyl, substituted or unsubstitutedpiperazinonyl, substituted or unsubstituted indolinyl, substituted orunsubstituted indolinonyl, substituted or unsubstituted1,2,3,4-tetrahydroquinolinyl, substituted or unsubstituted1,2,3,4-tetrahydroisoquinolinyl, substituted or unsubstituted3,4-dihydro-2(1H)-quinolinonyl, wherein if ring B is substituted thenring B is substituted with 1-3 R⁸.

In some embodiments, the compound has the structure of Formula (VII), ora pharmaceutically acceptable salt thereof:

-   -   wherein,    -   ring B is a monocyclic N-containing heterocycle or a bicyclic        N-containing heterocycle;    -   n is 0, 1, 2, or 3.

In some embodiments,

is

n is 0, 1, or 2.

In some embodiments,

is

In some embodiments, the compound has the structure of Formula (VIII),or a pharmaceutically acceptable salt thereof:

-   -   wherein,    -   L₁ is absent, —O— or —O—CH₂—;    -   L² is absent, —O—, —CH₂—O—, —C(═O)—, —C(═O)NR⁶—, —NR⁶—, or        —CH₂—C(═O)NR⁶—.

In some embodiments, the compound has the structure of Formula (IX), ora pharmaceutically acceptable salt thereof:

In some embodiments, L² is absent, —O—, —C(═O)NR⁶—, or —CH₂—C(═O)NR⁶—.

In some embodiments, the compound has the structure of Formula (X), or apharmaceutically acceptable salt thereof:

In some embodiments, the compound has the structure of Formula (XI), ora pharmaceutically acceptable salt thereof:

In some embodiments, L² is absent, —O—, —C(═O)NR⁶—, or —CH₂—C(═O)NR⁶—.

In some embodiments, the compound has the structure of Formula (XII), ora pharmaceutically acceptable salt thereof:

In one aspect, described herein is a compound of Formula (VI), or apharmaceutically acceptable salt thereof:

-   -   wherein,    -   each R¹ is independently H, D, or F;    -   R^(A) is H, D, halogen, —CN, —OR⁵, —SR⁵, —S(═O)R⁴, —S(═O)₂R⁴,        —S(═O)₂N(R⁵)₂, —NR²S(═O)₂R⁴, —C(═O)R⁴, —OC(═O)R⁴, —CO₂R⁵,        —OCO₂R⁵, —N(R⁵)₂, —OC(═O)N(R⁵)₂, —NR²C(═O)R⁴, —NR²C(═O)OR⁵, CH₃,        CH₂F, CHF₂, substituted or unsubstituted C₂-C₆alkyl,        C₁-C₆deuteroalkyl, C₁-C₆heteroalkyl, substituted or        unsubstituted C₃-C₁₀cycloalkyl, substituted or unsubstituted        C₂-C₁₀heterocycloalkyl, substituted or unsubstituted aryl, or        substituted or unsubstituted heteroaryl;    -   L¹ is absent, X¹, X¹—C₁-C₆alkylene, or C₁-C₆alkylene;    -   X¹ is —O—, —S—, —S(═O)—, —S(═O)₂—, —C(═O)—, —C(═O)O—,        —C(═O)NR²—, —NR²C(═O)—, or —NR²—;    -   R² is H, substituted or unsubstituted C₁-C₆alkyl,        C₁-C₆fluoroalkyl, or C₁-C₆deuteroalkyl;    -   each R³ is independently H, D, halogen, —CN, —OR⁵, —SR⁵,        —S(═O)R⁴, —S(═O)₂R⁴, —S(═O)₂N(R⁵)₂, —NR²S(═O)₂R⁴, —C(═O)R⁴,        —OC(═O)R⁴, —CO₂R⁵, —OCO₂R⁴, —N(R⁵)₂, —OC(═O)N(R⁵)₂, —NR²C(═O)R⁴,        —NR²C(═O)OR⁴, C₁-C₆alkyl, C₁-C₆fluoroalkyl, C₁-C₆deuteroalkyl,        C₁-C₆heteroalkyl, substituted or unsubstituted C₃-C₁₀cycloalkyl,        substituted or unsubstituted C₂-C₁₀heterocycloalkyl, substituted        or unsubstituted aryl, or substituted or unsubstituted        heteroaryl;    -   m is 0, 1, or 2;    -   each R⁴ is independently selected from C₁-C₆alkyl,        C₁-C₆fluoroalkyl, C₁-C₆deuteroalkyl, C₁-C₆heteroalkyl,        substituted or unsubstituted C₃-C₁₀cycloalkyl, substituted or        unsubstituted C₂-C₁₀heterocycloalkyl, substituted or        unsubstituted aryl, and substituted or unsubstituted heteroaryl;    -   each R⁵ is independently selected from H, C₁-C₆alkyl,        C₁-C₆fluoroalkyl, C₁-C₆deuteroalkyl, C₁-C₆heteroalkyl,        substituted or unsubstituted C₃-C₁₀cycloalkyl, substituted or        unsubstituted C₂-C₁₀heterocycloalkyl, substituted or        unsubstituted aryl, substituted or unsubstituted heteroaryl,        —C₁-C₄alkylene-(substituted or unsubstituted C₃-C₈cycloalkyl),        substituted or unsubstituted C₂-C₈heterocycloalkyl,        —C₁-C₄alkylene-(substituted or unsubstituted        C₂-C₈heterocycloalkyl), substituted or unsubstituted aryl,        —C₁-C₄alkylene-(substituted or unsubstituted aryl), substituted        or unsubstituted heteroaryl, and —C₁-C₄alkylene-(substituted or        unsubstituted heteroaryl); or two R⁵ on the same N atom are        taken together with the N atom to which they are attached to a        substituted or unsubstituted N-containing heterocycle;    -   Ring A is monocyclic carbocycle, bicyclic carbocycle, monocyclic        heterocycle, or bicyclic heterocycle;    -   R⁶ is H, C₁-C₆alkyl, C₁-C₆fluoroalkyl, or C₁-C₆deuteroalkyl;    -   Q is substituted or unsubstituted C₁-C₆alkyl, substituted or        unsubstituted C₁-C₆fluoroalkyl, substituted or unsubstituted        C₁-C₆heteroalkyl, substituted or unsubstituted C₃-C₈cycloalkyl,        —C₁-C₄alkylene-(substituted or unsubstituted C₃-C₈cycloalkyl),        substituted or unsubstituted C₂-C₈heterocycloalkyl,        —C₁-C₄alkylene-(substituted or unsubstituted        C₂-C₈heterocycloalkyl), substituted or unsubstituted aryl,        —C₁-C₄alkylene-(substituted or unsubstituted aryl), substituted        or unsubstituted heteroaryl, or —C₁-C₄alkylene-(substituted or        unsubstituted heteroaryl); wherein if Q is substituted then Q is        substituted with one or more R⁸;    -   or Q and R⁶ are taken together with the N atom to which they are        attached to form ring B, wherein ring B is a substituted or        unsubstituted N-containing heterocycle, wherein if ring B is        substituted then ring B is substituted with 1-3 R⁸;    -   each R⁸ is independently D, halogen, CN, —OR⁵, —SR⁵, —S(═O)R⁴,        —S(═O)₂R⁴, —S(═O)₂N(R⁵)₂, NR⁵S(═O)₂R⁴, C(═O)R⁴, OC(═O)R⁴, CO₂R⁵,        OCO₂R⁴, N(R⁴)₂, OC(═O)N(R⁵)₂, —NHC(═O)R⁴, —NHC(═O)OR⁴,        C₁-C₆alkyl, C₁-C₆fluoroalkyl, C₁-C₆deuteroalkyl,        C₁-C₆heteroalkyl, substituted or unsubstituted C₃-C₁₀cycloalkyl,        substituted or unsubstituted C₂-C₁₀heterocycloalkyl, substituted        or unsubstituted aryl, or substituted or unsubstituted        heteroaryl;    -   or two R⁸ groups attached to the same carbon atom are taken        together with carbon atom to which they are attached to form        either a substituted or unsubstituted carbocycle or substituted        or unsubstituted heterocycle.

In some embodiments, R^(A) is H, D, F, Cl, Br, —CN, —OR⁵, —SR⁵,—S(═O)R⁴, —S(═O)₂R⁴, —S(═O)₂N(R⁵)₂, —NR²S(═O)₂R⁴, —CO₂R⁵, —N(R⁵)₂,—NR²C(═O)R⁴, C₁-C₆alkyl, substituted or unsubstituted C₃-C₆cycloalkyl,substituted or unsubstituted C₂-C₆heterocycloalkyl, substituted orunsubstituted phenyl, or substituted or unsubstituted monocyclicheteroaryl.

In some embodiments, R^(A) is H, D, F, Cl, Br, —CN, —OR⁵, —CO₂R⁵,—N(R⁵)₂, —NR²C(═O)R⁴, —CH₃, —CH₂CH₃, —CH(CH₃)₂, —C(CH₃)₃, cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, substituted or unsubstitutedmonocyclic C₂-C₆heterocycloalkyl, substituted or unsubstituted phenyl,or substituted or unsubstituted monocyclic heteroaryl.

In some embodiments, R^(A) is H.

In some embodiments, R¹ is H.

In some embodiments, each R¹ is H; L¹ is absent, X¹, orX¹—C₁-C₆alkylene.

In some embodiments, X¹ is —O—.

In some embodiments, L¹ is absent, —O—, or —O—CH₂—, —C(═O)—,—C(═O)NHCH₂—, —NHC(═O)—, —NHC(═O)CH₂—.

In some embodiments, L¹ is —O—, or —O—CH₂—.

In some embodiments, Ring A is monocyclic C₃-C₆carbocycle, bicyclicC₉-C₁₀carbocycle, monocyclic C₁-C₅heterocycle, bicyclicC₆-C₉heterocycle.

In some embodiments, Ring A is monocyclic C₃-C₆carbocycle. In someembodiments, Ring A is phenyl, cyclopropyl, cyclobutyl, cyclopentyl, orcyclohexyl. In some embodiments, Ring A is phenyl. In some embodiments,Ring A is,

In some embodiments, Ring A is

In some embodiments, Ring A is bicyclic C₉-C₁₀carbocycle. In someembodiments, Ring A is naphthyl, indanyl, indenyl, ortetrahyodronaphthyl.

In some embodiments, Ring A is a monocyclic heterocycle containing 1-4 Natoms and 0 or 1 O or S atom, monocyclic heterocycle containing 0-4 Natoms and 1 O or S atoms, bicyclic heterocycle containing 1-4 N atomsand 0 or 1 O or S atoms, or bicyclic heterocycle containing 0-4 N atomsand 1 O or S atoms.

In some embodiments, Ring A is pyrrolidinyl, pyrrolidinonyl,tetrahydrofuranyl, tetrahydrofuranonyl, dihydrofuranonyl,dihydrofuranyl, tetrahydrothienyl, oxazolidinonyl, tetrahydropyranyl,dihydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl,thiomorpholinyl, piperazinyl, aziridinyl, azetidinyl, oxetanyl,thietanyl, homopiperidinyl, oxepanyl, thiepanyl, oxazepinyl, diazepinyl,thiazepinyl, 1,2,3,6-tetrahydropyridinyl, indolinyl, indolinonyl,1,2,3,4-tetrahydroquinolinyl, 1,2,3,4-tetrahydroisoquinolinyl,3,4-dihydro-2(1H)-quinolinonyl, furanyl, pyrrolyl, oxazolyl, thiazolyl,imidazolyl, pyrazolyl, triazolyl, tetrazolyl, isoxazolyl, isothiazolyl,oxadiazolyl, thiadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl,pyridazinyl, triazinyl, quinolinyl, isoquinolinyl, quinazolinyl,quinoxalinyl, naphthyridinyl, indolyl, indazolyl, benzoxazolyl,benzisoxazolyl, benzofuranyl, benzothienyl, benzothiazolyl,benzimidazolyl, purinyl, cinnolinyl, phthalazinyl, pteridinyl,pyridopyrimidinyl, pyrazolopyrimidinyl, or azaindolyl.

In some embodiments, Ring A is pyrrolidinyl, pyrrolidinonyl,piperidinyl, piperazinyl, indolinyl, indolinonyl,1,2,3,4-tetrahydroquinolinyl, 1,2,3,4-tetrahydroisoquinolinyl,3,4-dihydro-2(1H)-quinolinonyl, pyrrolyl, imidazolyl, pyrazolyl,pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, indolyl, indazolyl, orbenzimidazolyl.

In some embodiments, Ring A is

In some embodiments, Ring A is

In some embodiments, Q is substituted or unsubstituted C₃-C₆cycloalkyl,—C₁-C₂alkylene-(substituted or unsubstituted C₃-C₆cycloalkyl),substituted or unsubstituted C₂-C₈heterocycloalkyl,—C₁-C₂alkylene-(substituted or unsubstituted C₂-C₈heterocycloalkyl),substituted or unsubstituted phenyl, —C₁-C₂alkylene-(substituted orunsubstituted phenyl), substituted or unsubstituted heteroaryl, or—C₁-C₂alkylene-(substituted or unsubstituted heteroaryl); wherein if Qis substituted then Q is substituted with one or more R⁸; or Q and R⁶are taken together with the N atom to which they are attached to formring B, wherein ring B is a substituted or unsubstituted monocyclicN-containing heterocycle, or a substituted or unsubstituted bicyclicN-containing heterocycle, wherein if ring B is substituted then ring Bis substituted with 1-3 R⁸.

In some embodiments, Q and R⁶ are taken together with the N atom towhich they are attached to form a ring B, wherein ring B is asubstituted or unsubstituted monocyclic N-containing heterocycle, or asubstituted or unsubstituted bicyclic N-containing heterocycle, whereinif ring B is substituted then ring B is substituted with 1-3 R⁸.

In some embodiments, Q and R⁶ are taken together with the N atom towhich they are attached to form a ring B, wherein ring B is asubstituted or unsubstituted aziridinyl, substituted or unsubstitutedazetidinyl, substituted or unsubstituted pyrrolidinyl, substituted orunsubstituted pyrrolidinonyl, substituted or unsubstituted piperidinyl,substituted or unsubstituted piperidinonyl, substituted or unsubstitutedmorpholinyl, substituted or unsubstituted thiomorpholinyl, substitutedor unsubstituted piperazinyl, substituted or unsubstitutedpiperazinonyl, substituted or unsubstituted indolinyl, substituted orunsubstituted indolinonyl, substituted or unsubstituted1,2,3,4-tetrahydroquinolinyl, substituted or unsubstituted1,2,3,4-tetrahydroisoquinolinyl, substituted or unsubstituted3,4-dihydro-2(1H)-quinolinonyl, wherein if ring B is substituted thenring B is substituted with 1-3 R⁸.

In some embodiments, the compound has the structure of Formula (VII), ora pharmaceutically acceptable salt thereof:

-   -   wherein,    -   ring B is a monocyclic N-containing heterocycle or a bicyclic        N-containing heterocycle;    -   n is 0, 1, 2, or 3.

In some embodiments,

is

n is 0, 1, or 2.

In some embodiments,

is

In some embodiments, the compound has the structure of Formula (X), or apharmaceutically acceptable salt thereof:

In some embodiments, the compound has the structure of Formula (XII), ora pharmaceutically acceptable salt thereof:

In some embodiments, the compound has the structure of Formula (VIII),or a pharmaceutically acceptable salt thereof:

-   -   wherein,    -   L₁ is absent, —O— or —O—CH₂—.

Any combination of the groups described above for the various variablesis contemplated herein. Throughout the specification, groups andsubstituents thereof are chosen by one skilled in the field to providestable moieties and compounds.

In one aspect, described herein is a pharmaceutical compositioncomprising a compound described herein, or a pharmaceutically acceptablesalt, or solvate thereof, and at least one pharmaceutically acceptableexcipient. In some embodiments, the pharmaceutical composition isformulated for administration to a mammal by intravenous administration,subcutaneous administration, oral administration, inhalation, nasaladministration, dermal administration, or ophthalmic administration. Insome embodiments, the pharmaceutical composition is formulated foradministration to a mammal by intravenous administration, subcutaneousadministration, or oral administration. In some embodiments, thepharmaceutical composition is formulated for administration to a mammalby oral administration. In some embodiments, the pharmaceuticalcomposition is in the form of a tablet, a pill, a capsule, a liquid, asuspension, a gel, a dispersion, a solution, an emulsion, an ointment,or a lotion. In some embodiments, the pharmaceutical composition is inthe form of a tablet, a pill, or a capsule.

In one aspect, described herein is a method of treating or preventingany one of the diseases or conditions described herein comprisingadministering a therapeutically effective amount of a compound describedherein, or a pharmaceutically acceptable salt, or solvate thereof, to amammal in need thereof.

In one aspect, described herein is a method for the treatment orprevention of fibrosis in a mammal comprising administering atherapeutically effective amount of a compound described herein, or apharmaceutically acceptable salt, or solvate thereof, to the mammal inneed thereof. In other embodiments, the fibrosis is amenable totreatment with a LOXL2 inhibitor. In some embodiments, the fibrosis islung fibrosis. In some embodiments, the method further comprisesadministering a second therapeutic agent to the mammal in addition tothe compound described herein, or a pharmaceutically acceptable salt, orsolvate thereof.

In any of the aforementioned aspects are further embodiments in whichthe effective amount of the compound described herein, or apharmaceutically acceptable salt thereof, is: (a) systemicallyadministered to the mammal; and/or (b) administered orally to themammal; and/or (c) intravenously administered to the mammal; and/or (d)administered by inhalation; and/or (e) t administered by nasaladministration; or and/or (f) administered by injection to the mammal;and/or (g) administered topically to the mammal; and/or (h) administeredby ophthalmic administration; and/or (i) administered rectally to themammal; and/or (j) adminstered non-systemically or locally to themammal.

In any of the aforementioned aspects are further embodiments comprisingsingle administrations of the effective amount of the compound,including further embodiments in which the compound is administered oncea day to the mammal or the compound is administered to the mammalmultiple times over the span of one day. In some embodiments, thecompound is administered on a continuous dosing schedule. In someembodiments, the compound is administered on a continuous daily dosingschedule.

In any of the aforementioned aspects involving the treatment of adisease or condition are further embodiments comprising administering atleast one additional agent in addition to the administration of acompound of Formula (I) described herein, or a pharmaceuticallyacceptable salt thereof. In various embodiments, each agent isadministered in any order, including simultaneously.

In any of the embodiments disclosed herein, the mammal is a human.

In some embodiments, compounds provided herein are administered to ahuman.

In some embodiments, compounds provided herein are orally administered.

Articles of manufacture, which include packaging material, a compounddescribed herein, or a pharmaceutically acceptable salt thereof, withinthe packaging material, and a label that indicates that the compound orcomposition, or a pharmaceutically acceptable salt, pharmaceuticallyactive metabolite, pharmaceutically acceptable prodrug, or apharmaceutically acceptable solvate thereof, is used for inhibiting theactivity of LOXL2, or for the treatment, prevention or amelioration ofone or more symptoms of a disease or condition that would benefit frominhibition or reduction of the LOXL2 activity, are provided.

Other objects, features and advantages of the compounds, methods andcompositions described herein will become apparent from the followingdetailed description. It should be understood, however, that thedetailed description and the specific examples, while indicatingspecific embodiments, are given by way of illustration only, sincevarious changes and modifications within the spirit and scope of theinstant disclosure will become apparent to those skilled in the art fromthis detailed description.

DETAILED DESCRIPTION OF THE INVENTION

Lysyl oxidase like-2 (LOXL2) is a member of the lysyl oxidase (LOX)family, which comprises Cu²⁺ and lysine tyrosylquinone (LTQ)-dependentamine oxidases. The family comprises five genes: lox (LOX), loxl1 (lysyloxidase like-1, LOXL1), loxl2 (LOXL2), loxl3 (lysyl oxidase like-3,LOXL3), and loxl4 (lysyl oxidase like-4, LOXL4). The LOX family is knownfor catalyzing the oxidative deamination of the ε-amino group of lysinesand hydroxylysines in collagen and elastin to promote crosslinking ofthese molecules. Crosslinking of collagen and elastin is essential formaintaining tensile strength of the extracellular matrix.

LOXL2 has been demonstrated to have intracellular functions aside fromits role in remodeling of the extracellular matrix. LOXL2 positivelyregulates the epithelial-to-mesenchymal transition (EMT) transducer,Snail1, by promoting Snail1 stability and functional activity. LOXL2contributes positively to the activation of the focal adhesion kinase(FAK) signaling pathway and participates in the organization of focaladhesion complexes. Silencing of LOXL2 gene leads to reacquisition ofepithelial cell polarity and decreases the migratory and invasiveability of mammary cell lines. The modulation of cell adhesion and cellpolarity has been reported to be mediated by intracellular LOXL2. LOXL2transcriptionally represses E-cadherin as well as tight junction andcell polarity genes by Snail1-dependent and Snail1-independentmechanisms. LOXL2 has been more recently described to be associated withchromatin and reported to be involved in histone H2 deamination, afunction that is dependent on the LOXL2 catalytic domain.

In some embodiments, the methods disclosed herein are methods forinhibiting intracellular LOXL2. In some embodiments, the methodsdisclosed herein are methods for inhibiting extracellular (secreted)LOXL2. In some embodiments, the methods disclosed herein are methods forinhibiting extracellular and intracellular LOXL2.

Fibrosis

LOXL2 has been shown to be involved in fibrotic processes. Fibroticprocesses include an excessive deposition of extracellular matrixcomponents, such as collagen, which alters the physical, biochemical andbiomechanical matrix properties leading to defective organ function andorgan failure. Tissue fibrosis is also associated with cancerprogression by direct promotion of cellular transformation andmetastasis. Tumors are typically stiffer than normal tissue and tumorrigidity influences tumor metastasis.

Excessive LOXL2 enzyme activity has been implicated in the increasedstiffness of tumors. Elevated LOXL2 is also associated with fibroticlesions from livers of patients suffering from Wilson disease andprimary biliary cirrhosis. Additionally, the administration of aLOXL2-specific monoclonal antibody AB0023 was efficacious in reducingdisease in a model of fibrosis. AB0023 was shown to inhibit theproduction of growth factors and of crosslinked collagenous matrix andTGF-beta signaling.

In some embodiments, disclosed herein are methods of treating fibrosiswith a compound disclosed herein.

“Fibrosis,” as used herein, refers to the accumulation of extracellularmatrix constituents that occurs following trauma, inflammation, tissuerepair, immunological reactions, cellular hyperplasia, and neoplasia.

In some embodiments, disclosed herein is a method of reducing fibrosisin a tissue comprising contacting a fibrotic cell or tissue with acompound disclosed herein, in an amount sufficient to decrease orinhibit the fibrosis. In some embodiments, the fibrosis includes afibrotic condition.

In some embodiments, the fibrosis comprises lung fibrosis, liverfibrosis, kidney fibrosis, cardiac fibrosis, peritoneal fibrosis, ocularfibrosis or cutaneous fibrosis. In some embodiments, the fibrosiscomprises lung fibrosis. In some embodiments, the fibrosis comprisesliver fibrosis. In some embodiments, the fibrosis comprises kidneyfibrosis. In some embodiments, the fibrosis comprises cardiac fibrosis.In some embodiments, the fibrosis comprises peritoneal fibrosis. In someembodiments, the fibrosis comprises ocular fibrosis. In someembodiments, the fibrosis comprises cutaneous fibrosis.

In some embodiments, reducing fibrosis, or treatment of a fibroticcondition, includes reducing or inhibiting one or more of: formation ordeposition of extracellular matrix proteins; the number of pro-fibroticcell types (e.g., fibroblast or immune cell numbers); cellular collagenor hydroxyproline content within a fibrotic lesion; expression oractivity of a fibrogenic protein; or reducing fibrosis associated withan inflammatory response.

In some embodiments, the fibrotic condition is a fibrotic condition ofthe lung.

In some embodiments, the fibrotic condition is a fibrotic condition ofthe liver.

In some embodiments, the fibrotic condition is a fibrotic condition ofthe heart.

In some embodiments, the fibrotic condition is a fibrotic condition ofthe kidney.

In some embodiments, the fibrotic condition is a fibrotic condition ofthe skin.

In some embodiments, the fibrotic condition is a fibrotic condition ofthe eye.

In some embodiments, the fibrotic condition is a fibrotic condition ofthe gastrointestinal tract.

In some embodiments, the fibrotic condition is a fibrotic condition ofthe bone marrow.

In some embodiments, the fibrotic condition is idiopathic. In someembodiments, the fibrotic condition is associated with (e.g., issecondary to) a disease (e.g., an infectious disease, an inflammatorydisease, an autoimmune disease, a malignant or cancerous disease, and/ora connective disease); a toxin; an insult (e.g., an environmental hazard(e.g., asbestos, coal dust, polycyclic aromatic hydrocarbons), cigarettesmoking, a wound); a medical treatment (e.g., surgical incision,chemotherapy or radiation), or a combination thereof.

In some embodiments, disclosed herein is a method for the treatment orprevention of fibrosis in a mammal comprising administering a LOXL2inhibitor described herein, or a pharmaceutically acceptable saltthereof, to the mammal in need thereof.

In some embodiments, disclosed herein is a method of improving lungfunction in a mammal comprising administering a LOXL2 inhibitordescribed herein, or a pharmaceutically acceptable salt thereof, to themammal in need thereof. In some embodiments, the mammal has beendiagnosed as having lung fibrosis.

In some embodiments, disclosed herein is a method of treating idopathicpulmonary fibrosis in a mammal comprising administering a LOXL2inhibitor described herein, or a pharmaceutically acceptable saltthereof, to the mammal in need thereof.

In some embodiments, disclosed herein is a method of controlling anabnormal accumulation or activation of cells, fibronectin, collagen orincreased fibroblast recruitment in a tissue of a mammal comprisingadministering a LOXL2 inhibitor described herein, or a pharmaceuticallyacceptable salt thereof, to the mammal in need thereof. In someembodiments, the abnormal accumulation or activation of cells,fibronectin, collagen or increased fibroblast recruitment in the tissueresults in fibrosis.

In some embodiments, disclosed herein is a method for the treatment orprevention of scleroderma in a mammal comprising administering a LOXL2inhibitor described herein, or a pharmaceutically acceptable saltthereof, to the mammal in need thereof.

In some embodiments, disclosed herein is a method for reducing undesiredor abnormal dermal thickening in a mammal comprising administering tomammal in need thereof a LOXL2 inhibitor described herein, or apharmaceutically acceptable salt thereof. In some embodiments, thedermal thickening is associated with scleroderma.

In some embodiments, described herein is a method of controlling anabnormal accumulation or activation of cells, fibronectin, collagen orincreased fibroblast recruitment in tissues of a mammal comprisingadministering to mammal in need thereof a LOXL2 inhibitor describedherein, or a pharmaceutically acceptable salt thereof. In someembodiments, the abnormal accumulation or activation of cells,fibronectin, collagen or increased fibroblast recruitment in the dermaltissues results in fibrosis. In some embodiments, described herein is amethod of reducing hydroxyproline content in tissues of a mammal withfibrosis comprising administering to mammal in need thereof a LOXL2inhibitor described herein, or a pharmaceutically acceptable saltthereof.

Cancer

LOXL2 has been shown to be involved in signaling related to cancer cellgrowth, adhesion, motility and invasion. Specifically, LOXL2 inducesepithelial-to-mesenchymal transition (EMT) of cells to promote tumorinvasion. LOXL2 is also upregulated in hypoxic tumor environments whichleads to enhanced invasion of tumor cells. LOXL2 has also been shown topromote angiogenesis in hypoxic tumor environments.

Increased LOXL2 expression is associated with poor prognosis in patientswith colon, esophageal tumors, oral squamous cell carcinomas, laryngealsquamous cell carcinomas, and head and neck squamous cell carcinomas.LOXL2 has been proposed to participate in cancers of the breast, colon,gastric, head and neck, lung, and melanoma.

In some embodiments, disclosed herein are methods of treating cancerwith a compound disclosed herein.

The term “cancer” as used herein, refers to an abnormal growth of cellsthat tend to proliferate in an uncontrolled way and, in some cases, tometastasize (spread). Types of cancer include, but are not limited to,solid tumors (such as those of the bladder, bowel, brain, breast,endometrium, heart, kidney, lung, liver, uterus, lymphatic tissue(lymphoma), ovary, pancreas or other endocrine organ (thyroid),prostate, skin (melanoma or basal cell cancer) or hematological tumors(such as the leukemias and lymphomas) at any stage of the disease withor without metastases.

Compounds

Compounds described herein, including pharmaceutically acceptable salts,prodrugs, active metabolites and pharmaceutically acceptable solvatesthereof, are LOXL2 inhibitors. In one aspect, described herein are LOXL2inhibitors and uses thereof. In some embodiments, the LOXL2 inhibitorsdescribed herein have the structure of Formula (I), or apharmaceutically acceptable salt thereof. In some embodiments, Lysyloxidase like-2 (LOXL2) inhibitors described herein are used in thetreatment or prevention of a disease or condition in a mammal that wouldbenefit from the inhibition or reduction of Lysyl oxidase like-2 (LOXL2)activity. In some embodiments, the disease or condition is fibrosis orcancer. In some embodiments, the LOXL2 inhibitor is a substitutedpyridinylmethylamine compound, or a pharmaceutically acceptable salt, orsolvate thereof. In some embodiments, the substitutedpyridinylmethylamine compound is a substituted pyridin-4-ylmethylaminecompound. In some embodiments, the substituted pyridin-4-ylmethylaminecompound is a compound of Formula (I), or a pharmaceutically acceptablesalt, or solvate thereof.

In some embodiments, the substituted pyridinylmethylamine compound, or apharmaceutically acceptable salt, or solvate thereof, has the structureof Formula (I), or a pharmaceutically acceptable salt, or solvatethereof:

-   -   wherein,    -   each R¹ is independently H, D, or F;    -   R^(A) is H, D, halogen, —CN, —OR⁵, —SR⁵, —S(═O)R⁴, —S(═O)₂R⁴,        —S(═O)₂N(R⁵)₂, —NR²S(═O)₂R⁴, —C(═O)R⁴, —OC(═O)R⁴, —CO₂R⁵,        —OCO₂R⁵, —N(R⁵)₂, —OC(═O)N(R⁵)₂, —NR²C(═O)R⁴, —NR²C(═O)OR⁵,        C₁-C₆alkyl, C₁-C₆deuteroalkyl, C₁-C₆heteroalkyl, substituted or        unsubstituted C₃-C₁₀cycloalkyl, substituted or unsubstituted        C₂-C₁₀heterocycloalkyl, substituted or unsubstituted aryl, or        substituted or unsubstituted heteroaryl;    -   R^(B) is H, D, halogen, —CN, —OR⁵, —SR⁵, —S(═O)R⁴, —S(═O)₂R⁴,        —S(═O)₂N(R⁵)₂, —NR²S(═O)₂R⁴, —C(═O)R⁴, —OC(═O)R⁴, —CO₂R⁵,        —OCO₂R⁵, —N(R⁵)₂, —OC(═O)N(R⁵)₂, —NR²C(═O)R⁴, —NR²C(═O)OR⁵,        C₁-C₆alkyl, C₁-C₆fluoroalkyl, C₁-C₆deuteroalkyl,        C₁-C₆heteroalkyl, substituted or unsubstituted C₃-C₁₀cycloalkyl,        substituted or unsubstituted C₂-C₁₀heterocycloalkyl, substituted        or unsubstituted aryl, or substituted or unsubstituted        heteroaryl;    -   or R^(B) is

-   -   -   L¹ is absent, X¹, X¹—C₁-C₆alkylene, or C₁-C₆alkylene;        -   X¹ is —O—, —S—, —S(═O)—, —S(═O)₂—, —C(═O)—, —C(═O)O—,            —C(═O)NR²—, —NR²C(═O)—, or —NR²—;        -   R² is H, substituted or unsubstituted C₁-C₆alkyl,            C₁-C₆fluoroalkyl, or C₁-C₆deuteroalkyl;        -   each R³ is independently H, D, halogen, —CN, —OR⁵, —SR⁵,            —S(═O)R⁴, —S(═O)₂R⁴, —S(═O)₂N(R⁵)₂, —NR²S(═O)₂R⁴, —C(═O)R⁴,            —OC(═O)R⁴, —CO₂R⁵, —OCO₂R⁴, —N(R⁵)₂, —OC(═O)N(R⁵)₂,            —NR²C(═O)R⁴, —NR²C(═O)OR⁴, C₁-C₆alkyl, C₁-C₆fluoroalkyl,            C₁-C₆deuteroalkyl, C₁-C₆heteroalkyl, substituted or            unsubstituted C₃-C₁₀cycloalkyl, substituted or unsubstituted            C₂-C₁₀heterocycloalkyl, substituted or unsubstituted aryl,            or substituted or unsubstituted heteroaryl;            -   m is 0, 1, or 2;        -   each R⁴ is independently selected from C₁-C₆alkyl,            C₁-C₆fluoroalkyl, C₁-C₆deuteroalkyl, C₁-C₆heteroalkyl,            substituted or unsubstituted C₃-C₁₀cycloalkyl, substituted            or unsubstituted C₂-C₁₀heterocycloalkyl, substituted or            unsubstituted aryl, and substituted or unsubstituted            heteroaryl;        -   each R⁵ is independently selected from H, C₁-C₆alkyl,            C₁-C₆fluoroalkyl, C₁-C₆deuteroalkyl, C₁-C₆heteroalkyl,            substituted or unsubstituted C₃-C₁₀cycloalkyl, substituted            or unsubstituted C₂-C₁₀heterocycloalkyl, substituted or            unsubstituted aryl, substituted or unsubstituted heteroaryl,            —C₁-C₄alkylene-(substituted or unsubstituted            C₃-C₈cycloalkyl), substituted or unsubstituted            C₂-C₈heterocycloalkyl, —C₁-C₄alkylene-(substituted or            unsubstituted C₂-C₈heterocycloalkyl), substituted or            unsubstituted aryl, —C₁-C₄alkylene-(substituted or            unsubstituted aryl), substituted or unsubstituted            heteroaryl, and —C₁-C₄alkylene-(substituted or unsubstituted            heteroaryl); or two R⁵ on the same N atom are taken together            with the N atom to which they are attached to a substituted            or unsubstituted N-containing heterocycle;        -   Ring A is monocyclic carbocycle, bicyclic carbocycle,            monocyclic heterocycle, or bicyclic heterocycle;        -   L² is absent, —X²—, or —C₁-C₆alkylene-X²—;            -   X² is —O—, —S—, —S(═O)—, —S(═O)₂—, —S(═O)₂NR⁶—, —C(═O)—,                —C(═O)O—, —C(═O)NR⁶—, —NR⁶C(═O)—, —NR⁶S(═O)₂—, or —NR⁶—;            -   R⁶ is H, C₁-C₆alkyl, C₁-C₆fluoroalkyl, or                C₁-C₆deuteroalkyl;            -   Q is H, substituted or unsubstituted C₁-C₆alkyl,                substituted or unsubstituted C₁-C₆fluoroalkyl,                substituted or unsubstituted C₁-C₆heteroalkyl,                substituted or unsubstituted C₃-C₈cycloalkyl,                —C₁-C₄alkylene-(substituted or unsubstituted                C₃-C₈cycloalkyl), substituted or unsubstituted                C₂-C₈heterocycloalkyl, —C₁-C₄alkylene-(substituted or                unsubstituted C₂-C₈heterocycloalkyl), substituted or                unsubstituted aryl, —C₁-C₄alkylene-(substituted or                unsubstituted aryl), substituted or unsubstituted                heteroaryl, or —C₁-C₄alkylene-(substituted or                unsubstituted heteroaryl); wherein if Q is substituted                then Q is substituted with one or more R⁸;            -   or Q and R⁶ are taken together with the N atom to which                they are attached to form ring B, wherein ring B is a                substituted or unsubstituted N-containing heterocycle,                wherein if ring B is substituted then ring B is                substituted with 1-3 R⁸;            -   each R⁸ is independently D, halogen, CN, —OR⁵, —SR⁵,                —S(═O)R⁴, —S(═O)₂R⁴, —S(═O)₂N(R⁵)₂, NR⁵S(═O)₂R⁴,                C(═O)R⁴, OC(═O)R⁴, CO₂R⁵, OCO₂R⁴, N(R⁴)₂, OC(═O)N(R⁵)₂,                —NHC(═O)R⁴, —NHC(═O)OR⁴, C₁-C₆alkyl, C₁-C₆fluoroalkyl,                C₁-C₆deuteroalkyl, C₁-C₆heteroalkyl, substituted or                unsubstituted C₃-C₁₀cycloalkyl, substituted or                unsubstituted C₂-C₁₀heterocycloalkyl, substituted or                unsubstituted aryl, or substituted or unsubstituted                heteroaryl;            -   or two R⁸ groups attached to the same carbon atom are                taken together with carbon atom to which they are                attached to form either a substituted or unsubstituted                carbocycle or substituted or unsubstituted heterocycle.

For any and all of the embodiments, substituents are selected from amonga subset of the listed alternatives. For example, in some embodiments,each R¹ is independently H, D, or F. In some other embodiments, each R¹is independently H, or F. In other embodiments, each R¹ is H. In someembodiments, each R¹ is D. In some embodiments, each R¹ is F.

In some embodiments, the compound of Formula (I) has the followingstructure:

In some embodiments, R^(A) is H, D, F, Cl, Br, —CN, —OR⁵, —SR⁵,—S(═O)R⁴, —S(═O)₂R⁴, —S(═O)₂N(R⁵)₂, —NR²S(═O)₂R⁴, —CO₂R⁵, —N(R⁵)₂,—NR²C(═O)R⁴, C₁-C₆alkyl, substituted or unsubstituted C₃-C₆cycloalkyl,substituted or unsubstituted C₂-C₆heterocycloalkyl, substituted orunsubstituted phenyl, or substituted or unsubstituted monocyclicheteroaryl. In some embodiments, R^(A) is H, D, F, Cl, Br, —CN, —OR⁵,—CO₂R⁵, —N(R⁵)₂, —NR²C(═O)R⁴, —CH₃, —CH₂CH₃, —CH(CH₃)₂, —C(CH₃)₃,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, substituted orunsubstituted monocyclic C₂-C₆heterocycloalkyl, substituted orunsubstituted phenyl, or substituted or unsubstituted monocyclicheteroaryl. In some embodiments, R^(A) is H, D, F, Cl, Br, —CN, —OR⁵,—CO₂R⁵, —CH₃, —CH₂CH₃, —CH(CH₃)₂, —C(CH₃)₃, cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, substituted or unsubstituted phenyl, orsubstituted or unsubstituted monocyclic heteroaryl. In some embodiments,R^(A) is H, D, F, Cl, Br, —CN, —OR⁵, —CO₂R⁵, —CH₃, —CH₂CH₃, —CH(CH₃)₂,or —C(CH₃)₃. In some embodiments, R^(A) is H.

In some embodiments, the compound of Formula (I) has the followingstructure of Formula (II):

In some embodiments, R^(B) is H, D, F, Cl, Br, I, —CN, —OR⁵, —SR⁵,—S(═O)R⁴, —S(═O)₂R⁴, —S(═O)₂N(R⁵)₂, —NR²S(═O)₂R⁴, —C(═O)R⁴, —OC(═O)R⁴,—CO₂R⁵, —N(R⁵)₂, —NR²C(═O)R⁴, C₁-C₆alkyl, C₁-C₆fluoroalkyl,C₁-C₆deuteroalkyl, C₁-C₆heteroalkyl, substituted or unsubstitutedC₃-C₆cycloalkyl, substituted or unsubstituted monocyclicC₂-C₆heterocycloalkyl, substituted or unsubstituted phenyl, orsubstituted or unsubstituted monocyclic heteroaryl. In some embodiments,R^(B) is H, D, F, Cl, —CN, —OR⁵, —SR⁵, —NR²S(═O)₂R⁴, —CO₂R⁵, —N(R⁵)₂,—NR²C(═O)R⁴, C₁-C₆alkyl, C₁-C₆fluoroalkyl, substituted or unsubstitutedC₃-C₆cycloalkyl, substituted or unsubstituted monocyclicC₂-C₆heterocycloalkyl, substituted or unsubstituted phenyl, orsubstituted or unsubstituted monocyclic heteroaryl. In some embodiments,R^(B) is H, D, F, Cl, —CN, —OR⁵, —SR⁵, —CO₂R⁵, —N(R⁵)₂, —NR²C(═O)R⁴,C₁-C₄alkyl, C₁-C₄fluoroalkyl, substituted or unsubstitutedC₃-C₆cycloalkyl, substituted or unsubstituted monocyclicC₂-C₆heterocycloalkyl, substituted or unsubstituted phenyl, orsubstituted or unsubstituted monocyclic heteroaryl.

In some embodiments, or R^(B) is

In some embodiments, the compound has the following structure of Formula(III):

In some embodiments, L¹ is absent, X¹, X¹—C₁-C₄alkylene, orC₁-C₄alkylene. In some embodiments, L¹ is absent, X¹, orX¹—C₁-C₄alkylene. In some embodiments, L¹ is absent, or X¹. In someembodiments, L¹ is X¹. In some embodiments, L¹ is X¹—C₁-C₄alkylene.

In some embodiments, each R¹ is H; L¹ is absent, X¹, orX¹—C₁-C₆alkylene.

In some embodiments, X¹ is —O—.

In some embodiments, L¹ is absent, —O—, or —O—CH₂—, —C(═O)—,—C(═O)NHCH₂—, —NHC(═O)—, —NHC(═O)CH₂—.

In some embodiments, the compound has the structure of Formula (IV), ora pharmaceutically acceptable salt thereof:

In some embodiments, L¹ is —O—, or —O—CH₂—.

In some embodiments, the compound has the structure of Formula (V), or apharmaceutically acceptable salt thereof:

In some embodiments, Ring A is monocyclic C₃-C₆carbocycle, bicyclicC₉-C₁₀carbocycle, monocyclic C₁-C₅heterocycle, bicyclicC₆-C₉heterocycle. In some embodiments, Ring A is monocyclicC₃-C₆carbocycle. In some embodiments, Ring A is phenyl, cyclopropyl,cyclobutyl, cyclopentyl, or cyclohexyl. In some embodiments, Ring A isphenyl.

In some embodiments, Ring A is

In some embodiments, Ring A is

In some embodiments, Ring A is bicyclic C₉-C₁₀carbocycle. In someembodiments, Ring A is naphthyl, indanyl, indenyl, ortetrahyodronaphthyl.

In some embodiments, Ring A is a monocyclic heterocycle containing 1-4 Natoms and 0 or 1 O or S atom, monocyclic heterocycle containing 0-4 Natoms and 1 O or S atoms, bicyclic heterocycle containing 1-4 N atomsand 0 or 1 O or S atoms, or bicyclic heterocycle containing 0-4 N atomsand 1 O or S atoms.

In some embodiments, Ring A is pyrrolidinyl, pyrrolidinonyl,tetrahydrofuranyl, tetrahydrofuranonyl, dihydrofuranonyl,dihydrofuranyl, tetrahydrothienyl, oxazolidinonyl, tetrahydropyranyl,dihydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl,thiomorpholinyl, piperazinyl, aziridinyl, azetidinyl, oxetanyl,thietanyl, homopiperidinyl, oxepanyl, thiepanyl, oxazepinyl, diazepinyl,thiazepinyl, 1,2,3,6-tetrahydropyridinyl, indolinyl, indolinonyl,1,2,3,4-tetrahydroquinolinyl, 1,2,3,4-tetrahydroisoquinolinyl,3,4-dihydro-2(1H)-quinolinonyl, furanyl, pyrrolyl, oxazolyl, thiazolyl,imidazolyl, pyrazolyl, triazolyl, tetrazolyl, isoxazolyl, isothiazolyl,oxadiazolyl, thiadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl,pyridazinyl, triazinyl, quinolinyl, isoquinolinyl, quinazolinyl,quinoxalinyl, naphthyridinyl, indolyl, indazolyl, benzoxazolyl,benzisoxazolyl, benzofuranyl, benzothienyl, benzothiazolyl,benzimidazolyl, purinyl, cinnolinyl, phthalazinyl, pteridinyl,pyridopyrimidinyl, pyrazolopyrimidinyl, or azaindolyl.

In some embodiments, Ring A is pyrrolidinyl, pyrrolidinonyl,piperidinyl, piperazinyl, indolinyl, indolinonyl,1,2,3,4-tetrahydroquinolinyl, 1,2,3,4-tetrahydroisoquinolinyl,3,4-dihydro-2(1H)-quinolinonyl, pyrrolyl, imidazolyl, pyrazolyl,pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, indolyl, indazolyl, orbenzimidazolyl.

In some embodiments, Ring A is

In some embodiments, Ring A is

In some embodiments, L² is absent, —O—, —CH₂—O—, —C(═O)—, —C(═O)NR⁶—,—NR⁶C(═O)—, —NR⁶—, or —CH₂—C(═O)NR⁶—.

In some embodiments, Q is H, substituted or unsubstituted C₁-C₆alkyl,substituted or unsubstituted C₁-C₆fluoroalkyl, substituted orunsubstituted C₁-C₆heteroalkyl, substituted or unsubstitutedC₃-C₆cycloalkyl, —C₁-C₂alkylene-(substituted or unsubstitutedC₃-C₆cycloalkyl), substituted or unsubstituted C₂-C₈heterocycloalkyl,—C₁-C₂alkylene-(substituted or unsubstituted C₂-C₈heterocycloalkyl),substituted or unsubstituted phenyl, —C₁-C₂alkylene-(substituted orunsubstituted phenyl), substituted or unsubstituted heteroaryl, or—C₁-C₂alkylene-(substituted or unsubstituted heteroaryl); wherein if Qis substituted then Q is substituted with one or more R⁸; or Q and R⁶are taken together with the N atom to which they are attached to formring B, wherein ring B is a substituted or unsubstituted monocyclicN-containing heterocycle, or a substituted or unsubstituted bicyclicN-containing heterocycle, wherein if ring B is substituted then ring Bis substituted with 1-3 R⁸.

In some embodiments, Q is substituted or unsubstituted C₃-C₆cycloalkyl,—C₁-C₂alkylene-(substituted or unsubstituted C₃-C₆cycloalkyl),substituted or unsubstituted C₂-C₈heterocycloalkyl,—C₁-C₂alkylene-(substituted or unsubstituted C₂-C₈heterocycloalkyl),substituted or unsubstituted phenyl, —C₁-C₂alkylene-(substituted orunsubstituted phenyl), substituted or unsubstituted heteroaryl, or—C₁-C₂alkylene-(substituted or unsubstituted heteroaryl); wherein if Qis substituted then Q is substituted with one or more R⁸; or Q and R⁶are taken together with the N atom to which they are attached to formring B, wherein ring B is a substituted or unsubstituted monocyclicN-containing heterocycle, or a substituted or unsubstituted bicyclicN-containing heterocycle, wherein if ring B is substituted then ring Bis substituted with 1-3 R⁸.

In some embodiments, L² is —C(═O)NR⁶—, or —CH₂—C(═O)NR⁶—; Q is H,substituted or unsubstituted C₁-C₆alkyl, substituted or unsubstitutedC₁-C₆fluoroalkyl, substituted or unsubstituted C₁-C₆heteroalkyl,substituted or unsubstituted C₃-C₆cycloalkyl,—C₁-C₂alkylene-(substituted or unsubstituted C₃-C₆cycloalkyl),substituted or unsubstituted C₂-C₈heterocycloalkyl,—C₁-C₂alkylene-(substituted or unsubstituted C₂-C₈heterocycloalkyl),substituted or unsubstituted phenyl, —C₁-C₂alkylene-(substituted orunsubstituted phenyl), substituted or unsubstituted heteroaryl, or—C₁-C₂alkylene-(substituted or unsubstituted heteroaryl); wherein if Qis substituted then Q is substituted with one or more R⁸; or Q and R⁶are taken together with the N atom to which they are attached to formring B, wherein ring B is a substituted or unsubstituted monocyclicN-containing heterocycle, or a substituted or unsubstituted bicyclicN-containing heterocycle, wherein if ring B is substituted then ring Bis substituted with 1-3 R⁸.

In some embodiments, the compound described herein has the structure ofFormula (VI), or a pharmaceutically acceptable salt thereof:

In some embodiments, -L²-Q is —C(═O)NR⁶-Q; Q and R⁶ are taken togetherwith the N atom to which they are attached to form a ring B, whereinring B is a substituted or unsubstituted monocyclic N-containingheterocycle, or a substituted or unsubstituted bicyclic N-containingheterocycle, wherein if ring B is substituted then ring B is substitutedwith 1-3 R⁸.

In some embodiments, Q and R⁶ are taken together with the N atom towhich they are attached to form a ring B, wherein ring B is asubstituted or unsubstituted aziridinyl, substituted or unsubstitutedazetidinyl, substituted or unsubstituted pyrrolidinyl, substituted orunsubstituted pyrrolidinonyl, substituted or unsubstituted piperidinyl,substituted or unsubstituted piperidinonyl, substituted or unsubstitutedmorpholinyl, substituted or unsubstituted thiomorpholinyl, substitutedor unsubstituted piperazinyl, substituted or unsubstitutedpiperazinonyl, substituted or unsubstituted indolinyl, substituted orunsubstituted indolinonyl, substituted or unsubstituted1,2,3,4-tetrahydroquinolinyl, substituted or unsubstituted1,2,3,4-tetrahydroisoquinolinyl, substituted or unsubstituted3,4-dihydro-2(1H)-quinolinonyl, wherein if ring B is substituted thenring B is substituted with 1-3 R⁸.

In some embodiments, the compound has the structure of Formula (VII), ora pharmaceutically acceptable salt thereof:

-   -   wherein,    -   ring B is a monocyclic N-containing heterocycle or a bicyclic        N-containing heterocycle;    -   n is 0, 1, 2, or 3.

In some embodiments,

is

n is 0, 1, or 2.

In some embodiments,

is

In some embodiments, the compound has the structure of Formula (VIII),or a pharmaceutically acceptable salt thereof:

-   -   wherein,    -   L₁ is absent, —O— or —O—CH₂—;    -   L² is absent, —O—, —CH₂—O—, —C(═O)—, —C(═O)NR⁶—, —NR⁶—, or        —CH₂—C(═O)NR⁶—.

In some embodiments, the compound has the structure of Formula (IX), ora pharmaceutically acceptable salt thereof:

In some embodiments, L² is absent, —O—, —C(═O)NR⁶—, or —CH₂—C(═O)NR⁶—.

In some embodiments, the compound has the structure of Formula (X), or apharmaceutically acceptable salt thereof:

In some embodiments, the compound has the structure of Formula (XI), ora pharmaceutically acceptable salt thereof:

In some embodiments, L² is absent, —O—, —C(═O)NR⁶—, or —CH₂—C(═O)NR⁶—.

In some embodiments, the compound has the structure of Formula (XII), ora pharmaceutically acceptable salt thereof:

In one aspect, described herein is a compound of Formula (VI), or apharmaceutically acceptable salt thereof:

-   -   wherein,    -   each R¹ is independently H, D, or F;    -   R^(A) is H, D, halogen, —CN, —OR⁵, —SR⁵, —S(═O)R⁴, —S(═O)₂R⁴,        —S(═O)₂N(R⁵)₂, —NR²S(═O)₂R⁴, —C(═O)R⁴, —OC(═O)R⁴, —CO₂R⁵,        —OCO₂R⁵, —N(R⁵)₂, —OC(═O)N(R⁵)₂, —NR²C(═O)R⁴, —NR²C(═O)OR⁵,        C₁-C₆alkyl, C₁-C₆deuteroalkyl, C₁-C₆heteroalkyl, substituted or        unsubstituted C₃-C₁₀cycloalkyl, substituted or unsubstituted        C₂-C₁₀heterocycloalkyl, substituted or unsubstituted aryl, or        substituted or unsubstituted heteroaryl;    -   L¹ is absent, X¹, X¹—C₁-C₆alkylene, or C₁-C₆alkylene;    -   X¹ is —O—, —S—, —S(═O)—, —S(═O)₂—, —C(═O)—, —C(═O)O—,        —C(═O)NR²—, —NR²C(═O)—, or —NR²—;    -   R² is H, substituted or unsubstituted C₁-C₆alkyl,        C₁-C₆fluoroalkyl, or C₁-C₆deuteroalkyl;    -   each R³ is independently H, D, halogen, —CN, —OR⁵, —SR⁵,        —S(═O)R⁴, —S(═O)₂R⁴, —S(═O)₂N(R⁵)₂, —NR²S(═O)₂R⁴, —C(═O)R⁴,        —OC(═O)R⁴, —CO₂R⁵, —OCO₂R⁴, —N(R⁵)₂, —OC(═O)N(R⁵)₂, —NR²C(═O)R⁴,        —NR²C(═O)OR⁴, C₁-C₆alkyl, C₁-C₆fluoroalkyl, C₁-C₆deuteroalkyl,        C₁-C₆heteroalkyl, substituted or unsubstituted C₃-C₁₀cycloalkyl,        substituted or unsubstituted C₂-C₁₀heterocycloalkyl, substituted        or unsubstituted aryl, or substituted or unsubstituted        heteroaryl;    -   m is 0, 1, or 2;    -   each R⁴ is independently selected from C₁-C₆alkyl,        C₁-C₆fluoroalkyl, C₁-C₆deuteroalkyl, C₁-C₆heteroalkyl,        substituted or unsubstituted C₃-C₁₀cycloalkyl, substituted or        unsubstituted C₂-C₁₀heterocycloalkyl, substituted or        unsubstituted aryl, and substituted or unsubstituted heteroaryl;    -   each R⁵ is independently selected from H, C₁-C₆alkyl,        C₁-C₆fluoroalkyl, C₁-C₆deuteroalkyl, C₁-C₆heteroalkyl,        substituted or unsubstituted C₃-C₁₀cycloalkyl, substituted or        unsubstituted C₂-C₁₀heterocycloalkyl, substituted or        unsubstituted aryl, substituted or unsubstituted heteroaryl,        —C₁-C₄alkylene-(substituted or unsubstituted C₃-C₈cycloalkyl),        substituted or unsubstituted C₂-C₈heterocycloalkyl,        —C₁-C₄alkylene-(substituted or unsubstituted        C₂-C₈heterocycloalkyl), substituted or unsubstituted aryl,        —C₁-C₄alkylene-(substituted or unsubstituted aryl), substituted        or unsubstituted heteroaryl, and —C₁-C₄alkylene-(substituted or        unsubstituted heteroaryl); or two R⁵ on the same N atom are        taken together with the N atom to which they are attached to a        substituted or unsubstituted N-containing heterocycle;    -   Ring A is monocyclic carbocycle, bicyclic carbocycle, monocyclic        heterocycle, or bicyclic heterocycle;    -   R⁶ is H, C₁-C₆alkyl, C₁-C₆fluoroalkyl, or C₁-C₆deuteroalkyl;    -   Q is substituted or unsubstituted C₁-C₆alkyl, substituted or        unsubstituted C₁-C₆fluoroalkyl, substituted or unsubstituted        C₁-C₆heteroalkyl, substituted or unsubstituted C₃-C₈cycloalkyl,        —C₁-C₄alkylene-(substituted or unsubstituted C₃-C₈cycloalkyl),        substituted or unsubstituted C₂-C₈heterocycloalkyl,        —C₁-C₄alkylene-(substituted or unsubstituted        C₂-C₈heterocycloalkyl), substituted or unsubstituted aryl,        —C₁-C₄alkylene-(substituted or unsubstituted aryl), substituted        or unsubstituted heteroaryl, or —C₁-C₄alkylene-(substituted or        unsubstituted heteroaryl); wherein if Q is substituted then Q is        substituted with one or more R⁸;    -   or Q and R⁶ are taken together with the N atom to which they are        attached to form ring B, wherein ring B is a substituted or        unsubstituted N-containing heterocycle, wherein if ring B is        substituted then ring B is substituted with 1-3 R⁸;    -   each R⁸ is independently D, halogen, CN, —OR⁵, —SR⁵, —S(═O)R⁴,        —S(═O)₂R⁴, —S(═O)₂N(R⁵)₂, NR⁵S(═O)₂R⁴, C(═O)R⁴, OC(═O)R⁴, CO₂R⁵,        OCO₂R⁴, N(R⁴)₂, OC(═O)N(R⁵)₂, —NHC(═O)R⁴, —NHC(═O)OR⁴,        C₁-C₆alkyl, C₁-C₆fluoroalkyl, C₁-C₆deuteroalkyl,        C₁-C₆heteroalkyl, substituted or unsubstituted C₃-C₁₀cycloalkyl,        substituted or unsubstituted C₂-C₁₀heterocycloalkyl, substituted        or unsubstituted aryl, or substituted or unsubstituted        heteroaryl;    -   or two R⁸ groups attached to the same carbon atom are taken        together with carbon atom to which they are attached to form        either a substituted or unsubstituted carbocycle or substituted        or unsubstituted heterocycle.

In some embodiments, R^(A) is H, D, F, Cl, Br, —CN, —OR⁵, —SR⁵,—S(═O)R⁴, —S(═O)₂R⁴, —S(═O)₂N(R⁵)₂, —NR²S(═O)₂R⁴, —CO₂R⁵, —N(R⁵)₂,—NR²C(═O)R⁴, C₁-C₆alkyl, substituted or unsubstituted C₃-C₆cycloalkyl,substituted or unsubstituted C₂-C₆heterocycloalkyl, substituted orunsubstituted phenyl, or substituted or unsubstituted monocyclicheteroaryl. In some embodiments, R^(A) is H, D, F, Cl, Br, —CN, —OR⁵,—CO₂R⁵, —N(R⁵)₂, —NR²C(═O)R⁴, —CH₃, —CH₂CH₃, —CH(CH₃)₂, —C(CH₃)₃,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, substituted orunsubstituted monocyclic C₂-C₆heterocycloalkyl, substituted orunsubstituted phenyl, or substituted or unsubstituted monocyclicheteroaryl. In some embodiments, R^(A) is H, D, F, Cl, Br, —CN, —OR⁵,—N(R⁵)₂, —NR²C(═O)R⁴, —CH₃, —CH₂CH₃, —CH(CH₃)₂, or —C(CH₃)₃. In someembodiments, R^(A) is H.

In some embodiments, R¹ is H.

In some embodiments, each R¹ is H; L¹ is absent, X¹, orX¹—C₁-C₆alkylene.

In some embodiments, X¹ is —O—.

In some embodiments, L¹ is absent, —O—, or —O—CH₂—, —C(═O)—,—C(═O)NHCH₂—, —NHC(═O)—, —NHC(═O)CH₂—.

In some embodiments, L¹ is —O—, or —O—CH₂—.

In some embodiments, Ring A is monocyclic C₃-C₆carbocycle, bicyclicC₅-C₁₂carbocycle, monocyclic C₁-C₅heterocycle, bicyclicC₅-C₁₀heterocycle.

In some embodiments, Ring A is monocyclic C₃-C₆carbocycle, bicyclicC₉-C₁₀carbocycle, monocyclic C₁-C₈heterocycle, bicyclicC₆-C₉heterocycle.

In some embodiments, Ring A is monocyclic C₃-C₆carbocycle. In someembodiments, Ring A is phenyl, cyclopropyl, cyclobutyl, cyclopentyl, orcyclohexyl. In some embodiments, Ring A is phenyl. In some embodiments,Ring A is

In some embodiments, Ring A is

In some embodiments, Ring A is a bicyclic C₅-C₁₂carbocycle. In someembodiments, Ring A is a bicyclic C₅-C₁₂carbocycle that is a fusedC₅-C₁₂carbocycle, bridged C₅-C₁₂carbocycle, or spirocyclicC₅-C₁₂carbocycle.

In some embodiments, Ring A is bicyclic C₉-C₁₀carbocycle. In someembodiments, Ring A is naphthyl, indanyl, indenyl, ortetrahyodronaphthyl.

In some embodiments, Ring A is a monocyclic heterocycle containing 1-4 Natoms and 0 or 1 O or S atom, monocyclic heterocycle containing 0-4 Natoms and 1 O or S atoms, bicyclic heterocycle containing 1-4 N atomsand 0 or 1 O or S atoms, or bicyclic heterocycle containing 0-4 N atomsand 1 O or S atoms.

In some embodiments, Ring A is pyrrolidinyl, pyrrolidinonyl,tetrahydrofuranyl, tetrahydrofuranonyl, dihydrofuranonyl,dihydrofuranyl, tetrahydrothienyl, oxazolidinonyl, tetrahydropyranyl,dihydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl,thiomorpholinyl, piperazinyl, aziridinyl, azetidinyl, oxetanyl,thietanyl, homopiperidinyl, oxepanyl, thiepanyl, oxazepinyl, diazepinyl,thiazepinyl, 1,2,3,6-tetrahydropyridinyl, indolinyl, indolinonyl,1,2,3,4-tetrahydroquinolinyl, 1,2,3,4-tetrahydroisoquinolinyl,3,4-dihydro-2(1H)-quinolinonyl, furanyl, pyrrolyl, oxazolyl, thiazolyl,imidazolyl, pyrazolyl, triazolyl, tetrazolyl, isoxazolyl, isothiazolyl,oxadiazolyl, thiadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl,pyridazinyl, triazinyl, quinolinyl, isoquinolinyl, quinazolinyl,quinoxalinyl, naphthyridinyl, indolyl, indazolyl, benzoxazolyl,benzisoxazolyl, benzofuranyl, benzothienyl, benzothiazolyl,benzimidazolyl, purinyl, cinnolinyl, phthalazinyl, pteridinyl,pyridopyrimidinyl, pyrazolopyrimidinyl, or azaindolyl.

In some embodiments, Ring A is pyrrolidinyl, pyrrolidinonyl,piperidinyl, piperazinyl, indolinyl, indolinonyl,1,2,3,4-tetrahydroquinolinyl, 1,2,3,4-tetrahydroisoquinolinyl,3,4-dihydro-2(1H)-quinolinonyl, pyrrolyl, imidazolyl, pyrazolyl,pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, indolyl, indazolyl, orbenzimidazolyl.

In some embodiments, Ring A is

In some embodiments, Ring A is a bicyclic C₅-C₁₀heterocycle containing1-4 N atoms and 0 or 1 O or S atoms, or bicyclic heterocycle containing0-4 N atoms and 1 O or S atoms that is a fused bicyclicC₅-C₁₀heterocycle, bridged bicyclic C₅-C₁₀ heterocycle, or spirobicyclic C₅-C₁₀heterocycle.

In some embodiments, Ring A is

In some embodiments, Ring A is

In some embodiments, Ring A is

In some embodiments, Ring A is

In some embodiments, Ring A is a bicyclic heterocycle containing 1-4 Natoms and 0 or 1 O or S atoms, or bicyclic heterocycle containing 0-4 Natoms and 1 O or S atoms.

In some embodiments, Ring A is a bicyclic C₅-C₁₀heterocycloalkylcontaining 1-4 N atoms and 0 or 1 O or S atoms, or bicyclic heterocyclecontaining 0-4 N atoms and 1 O or S atoms that is a fused bicyclicC₅-C₁₀heterocycloalkyl, bridged bicyclic C₅-C₁₀heterocycloalkyl, orspiro bicyclic C₅-C₁₀heterocycloalkyl.

In some embodiments, Ring A is a bridged bicyclic C₅-C₁₀heterocycloalkylthat is

In some embodiments, Ring A is spiro bicyclic C₅-C₁₀heterocycloalkylthat is

In some embodiments, Q is substituted or unsubstituted C₃-C₆cycloalkyl,—C₁-C₂alkylene-(substituted or unsubstituted C₃-C₆cycloalkyl),substituted or unsubstituted C₂-C₈heterocycloalkyl,—C₁-C₂alkylene-(substituted or unsubstituted C₂-C₈heterocycloalkyl),substituted or unsubstituted phenyl, —C₁-C₂alkylene-(substituted orunsubstituted phenyl), substituted or unsubstituted heteroaryl, or—C₁-C₂alkylene-(substituted or unsubstituted heteroaryl); wherein if Qis substituted then Q is substituted with one or more R⁸; or Q and R⁶are taken together with the N atom to which they are attached to formring B, wherein ring B is a substituted or unsubstituted monocyclicN-containing heterocycle, or a substituted or unsubstituted bicyclicN-containing heterocycle, wherein if ring B is substituted then ring Bis substituted with 1-3 R⁸.

In some embodiments, Q and R⁶ are taken together with the N atom towhich they are attached to form a ring B, wherein ring B is asubstituted or unsubstituted monocyclic N-containing heterocycle, or asubstituted or unsubstituted bicyclic N-containing heterocycle, whereinif ring B is substituted then ring B is substituted with 1-3 R⁸.

In some embodiments, Q and R⁶ are taken together with the N atom towhich they are attached to form a ring B, wherein ring B is asubstituted or unsubstituted aziridinyl, substituted or unsubstitutedazetidinyl, substituted or unsubstituted pyrrolidinyl, substituted orunsubstituted pyrrolidinonyl, substituted or unsubstituted piperidinyl,substituted or unsubstituted piperidinonyl, substituted or unsubstitutedmorpholinyl, substituted or unsubstituted thiomorpholinyl, substitutedor unsubstituted piperazinyl, substituted or unsubstitutedpiperazinonyl, substituted or unsubstituted indolinyl, substituted orunsubstituted indolinonyl, substituted or unsubstituted1,2,3,4-tetrahydroquinolinyl, substituted or unsubstituted1,2,3,4-tetrahydroisoquinolinyl, substituted or unsubstituted3,4-dihydro-2(1H)-quinolinonyl, wherein if ring B is substituted thenring B is substituted with 1-3 R⁸.

In some embodiments, —NR⁶Q is

In some embodiments, the compound has the structure of Formula (VII), ora pharmaceutically acceptable salt thereof:

-   -   wherein,    -   ring B is a monocyclic N-containing heterocycle or a bicyclic        N-containing heterocycle;    -   n is 0, 1, 2, or 3.

In some embodiments,

is

n is 0, 1, or 2.

In some embodiments,

is

In some embodiments,

is

In some embodiments,

is

In some embodiments,

is

In some embodiments,

is

In some embodiments,

is

In some embodiments, each R⁸ is independently D, F, Cl, CN, —OH, —OCH₃,—OCH₂CH₃, —S(═O)₂CH₃, —S(═O)₂NH₂, —S(═O)₂N(CH₃)₂, —C(═O)CH₃, OC(═O)CH₃,—CO₂H, —CO₂CH₃, —CO₂CH₂CH₃, —CO₂CH(CH₃)₂, —CO₂C(CH₃)₃, —NH₂, —N(CH₃)₂,—CH₃, —CH₂CH₃, —C≡CH, —CF₃, —CH₂CF₃, or —OCH₂OH.

In some embodiments, two R⁸ groups attached to the same carbon atom aretaken together with carbon atom to which they are attached to formeither a substituted or unsubstituted monocyclic 3 to 6 memberedcarbocycle or substituted or unsubstituted monocyclic 3 to 6 memberedheterocycle.

In some embodiments, the compound has the structure of Formula (X), or apharmaceutically acceptable salt thereof:

In some embodiments, the compound has the structure of Formula (XII), ora pharmaceutically acceptable salt thereof:

In some embodiments, the compound has the structure of Formula (VIII),or a pharmaceutically acceptable salt thereof:

-   -   wherein,    -   L₁ is absent, —O— or —O—CH₂—.

In some embodiments, the compound of Formula (I) has the followingstructure:

In some embodiments, -L¹- is as described in Table 1. In someembodiments,

is as described in Table 1. In some embodiments,

is as described in Table 1.

In some embodiments, the compound of Formula (I) has the followingstructure:

In some embodiments, -L¹- is as described in Table 2. In someembodiments,

is as described in Table 2. In some embodiments, -L²-Q is as describedin Table 2.

In some embodiments, the compound of Formula (I) has the followingstructure:

In some embodiments, R^(A) is as described in Table 3. In someembodiments, -L¹- is as described in Table 3. In some embodiments,

is as described in Table 3. In some embodiments, -L²-Q is as describedin Table 3.

In some embodiments, the compound of Formula (I) has the followingstructure:

In some embodiments, R^(A) is as described herein. In some embodiments,R^(A) is as described in Table 4.

In some embodiments, compounds of Formula (I) include, but are notlimited to, those described in Table 1.

TABLE 1

Compound Number —L¹—

1-1 —

1-2 (racemic) —

1-3 —

1-4 —

1-5 —

1-6 (racemic) —

1-7 —

1-8 —

1-9 —

1-10 —

1-11 O

1-12 (racemic) O

1-13 O

1-14 O

1-15 O

1-16 (racemic) O

1-17 O

1-18 O

1-19 O

1-20 O

1-21 O

1-22 O

1-23 O

1-24 O

1-25 O

1-26 O

1-27 O

1-28 O

1-29 O

1-30 O

1-31 O

1-32 O

1-33 O

1-34 O

1-35 O

1-36 O

1-37 O

1-38 O

1-39 O

1-40 O

1-41 O

1-42 O

1-43 O

1-44 O

1-45 OCH₂

In some embodiments, described herein is a compound that is:

-   4-(4-(Aminomethyl)pyridin-2-yl)-N-(2-methoxyethyl)benzamide    (Compound 1-1);-   Racemic-(4-(4-(aminomethyl)pyridin-2-yl)phenyl)(3-hydroxy-3-(trifluoromethyl)pyrrolidin-1-yl)methanone    (Compound 1-2);-   4-(4-(Aminomethyl)pyridin-2-yl)-N-phenylbenzamide (Compound 1-3);-   4-(4-(Aminomethyl)pyridin-2-yl)-N-benzylbenzamide (Compound 1-4);-   3-(4-(Aminomethyl)pyridin-2-yl)-N-(2-methoxyethyl)benzamide    (Compound 1-5);-   Racemic-(3-(4-(aminomethyl)pyridin-2-yl)phenyl)(3-hydroxy-3-(trifluoromethyl)pyrrolidin-1-yl)methanone    (Compound 1-6);-   3-(4-(Aminomethyl)pyridin-2-yl)-N-phenylbenzamide (Compound 1-7);-   3-(4-(Aminomethyl)pyridin-2-yl)-N-benzylbenzamide (Compound 1-8);-   3-(4-(Aminomethyl)pyridin-2-yl)-N-(5-chloro-2-methylphenyl)benzamide    (Compound 1-9);-   3-(4-(Aminomethyl)pyridin-2-yl)-N-(6-chloro-1H-indol-4-yl)benzamide    (Compound 1-10);-   4-((4-(Aminomethyl)pyridin-2-yl)oxy)-N-(2-methoxyethyl)benzamide    (Compound 1-11);-   Racemic-4-((4-(aminomethyl)pyridin-2-yl)oxy)phenyl)(3-hydroxy-3-(trifluoromethyl)pyrrolidin-1-yl)methanone    (Compound 1-12);-   4-((4-(Aminomethyl)pyridin-2-yl)oxy)-N-phenylbenzamide (Compound    1-13);-   4-((4-(Aminomethyl)pyridin-2-yl)oxy)-N-benzylbenzamide (Compound    1-14);-   3-((4-(Aminomethyl)pyridin-2-yl)oxy)-N-(2-methoxyethyl)benzamide    (Compound 1-15);-   Racemic-(3-((4-(aminomethyl)pyridin-2-yl)oxy)phenyl)(3-hydroxy-3-(trifluoromethyl)pyrrolidin-1-yl)methanone    (Compound 1-16);-   3-((4-(Aminomethyl)pyridin-2-yl)oxy)-N-phenylbenzamide (Compound    1-17);-   3-((4-(Aminomethyl)pyridin-2-yl)oxy)-N-benzylbenzamide (Compound    1-18);-   3-((4-(Aminomethyl)pyridin-2-yl)oxy)-N-(3-methoxyphenyl)benzamide    (Compound 1-19);-   3-((4-(Aminomethyl)pyridin-2-yl)oxy)-N-(4-methoxyphenyl)benzamide    (Compound 1-20);-   3-((4-(Aminomethyl)pyridin-2-yl)oxy)-N-(3-(trifluoromethyl)phenyl)benzamide    (Compound 1-21);-   3-((4-(Aminomethyl)pyridin-2-yl)oxy)-N-(4-(trifluoromethyl)phenyl)benzamide    (Compound 1-22);-   3-((4-(Aminomethyl)pyridin-2-yl)oxy)-N-(4-fluorophenyl)benzamide    (Compound 1-23);-   3-((4-(Aminomethyl)pyridin-2-yl)oxy)-N-(2,4-difluorophenyl)benzamide    (Compound 1-24);-   3-((4-(Aminomethyl)pyridin-2-yl)oxy)-N-(4-bromophenyl)benzamide    (Compound 1-25);-   Methyl 4-(3-((4-(aminomethyl)pyridin-2-yl)oxy)benzamido)benzoate    (Compound 1-26);-   Ethyl 3-(3-((4-(aminomethyl)pyridin-2-yl)oxy)benzamido)benzoate    (Compound 1-27);-   3-(3-((4-(Aminomethyl)pyridin-2-yl)oxy)benzamido)benzoic acid    (Compound 1-28);-   4-(3-((4-(Aminomethyl)pyridin-2-yl)oxy)benzamido)benzoic acid    (Compound 1-29);-   3-((4-(Aminomethyl)pyridin-2-yl)oxy)-N-(2,4-difluorobenzyl)benzamide    (Compound 1-30);-   3-((4-(Aminomethyl)pyridin-2-yl)oxy)-N-(4-(trifluoromethyl)benzyl)benzamide    (Compound 1-31);-   3-((4-(Aminomethyl)pyridin-2-yl)oxy)-N-(4-bromobenzyl)benzamide    (Compound 1-32);-   Methyl    4-((3-((4-(aminomethyl)pyridin-2-yl)oxy)benzamido)methyl)benzoate    (Compound 1-33);-   4-((3-((4-(Aminomethyl)pyridin-2-yl)oxy)benzamido)methyl)benzoic    acid (Compound 1-34);-   3-((3-((4-(Aminomethyl)pyridin-2-yl)oxy)benzamido)methyl)benzoic    acid (Compound 1-35);-   (R)-3-((4-(Aminomethyl)pyridin-2-yl)oxy)-N-(2-hydroxy-1-phenylethyl)benzamide    (Compound 1-36);-   3-((4-(Aminomethyl)pyridin-2-yl)oxy)-N-(3-fluoro-4-(1H-imidazol-1-yl)benzyl)benzamide    (Compound 1-37);-   3-((4-(Aminomethyl)pyridin-2-yl)oxy)-N-(4-(4-ethylpiperazin-1-yl)benzyl)benzamide    (Compound 1-38);-   3-((4-(Aminomethyl)pyridin-2-yl)oxy)-N-(3-carbamimidoylbenzyl)benzamide    (Compound 1-39);-   3-((4-(Aminomethyl)pyridin-2-yl)oxy)-N-phenethylbenzamide (Compound    1-40);-   (3-((4-(Aminomethyl)pyridin-2-yl)oxy)phenyl)(3,4-dihydroisoquinolin-2(1H)-yl)methanone    (Compound 1-41);-   3-((4-(Aminomethyl)pyridin-2-yl)oxy)-N-(benzo[b]thiophen-2-ylmethyl)benzamide    (Compound 1-42);-   3-((4-(Aminomethyl)pyridin-2-yl)oxy)-N-(pyrazin-2-ylmethyl)benzamide    (Compound 1-43);-   3-((4-(Aminomethyl)pyridin-2-yl)oxy)-N-tridecylbenzamide (Compound    1-44);-   3-(((4-(Aminomethyl)pyridin-2-yl)oxy)methyl)-N-phenylbenzamide    (Compound 1-45); or a pharmaceutically acceptable salt thereof.

TABLE 2

Compound Number —L¹—

—L²—Q 2-1 (racemic trans) —

— 2-2 (racemic) —

— 2-3 —

— 2-4 —

— 2-5 —

— 2-6 —

— 2-7 O

— 2-8 O

2-9 O

— 2-10 O

2-11 O

2-12 O

2-13 O

2-14 O

2-15 O

2-16 O

2-17 O

2-18 O

2-19 O

2-20 O

2-21 O

2-22 O

2-23 O

2-24 O

2-25 O

2-26 O

2-27 O

2-28 (enant-1) O

2-29 (enant-2) O

2-30 O

2-31 O

2-32 O

— 2-33 O

2-34 O

2-35 O

2-36 O

2-37 O

2-38 O

2-39 O

2-40 (racemic) C(═O)

— 2-41 C(═O)NHCH₂

— 2-42 NHC(═O)

— 2-43 NHC(═O)CH₂

—

In some embodiments, described herein is a compound that is:

-   Racemic-trans-(1-(4-(aminomethyl)pyridin-2-yl)-4-fluoropyrrolidin-3-ol    (Compound 2-1);-   Racemic-1-(4-(aminomethyl)pyridin-2-yl)-3-(trifluoromethyl)pyrrolidin-3-ol    (Compound 2-2);-   [2,3′-Bipyridin]-4-ylmethanamine (Compound 2-3);-   (2-(4-Fluorophenyl)pyridin-4-yl)methanamine (Compound 2-4);-   3-((4-(Aminomethyl)pyridin-2-yl)oxy)benzoic acid (Compound 2-5);-   4-(4-(Aminomethyl)pyridin-2-yl)benzoic acid (Compound 2-6);-   (2-Phenoxypyridin-4-yl)methanamine (Compound 2-7);-   (2-(3-Phenoxyphenoxy)pyridin-4-yl)methanamine (Compound 2-8);-   4-((4-(Aminomethyl)pyridin-2-yl)oxy)benzoic acid (Compound 2-9);-   (2-((1-Benzyl-1H-indol-4-yl)oxy)pyridin-4-yl)methanamine (Compound    2-10);-   (2-((1-(2,4-Difluorobenzyl)-2-methyl-1H-indol-4-yl)oxy)pyridin-4-yl)methanamine    (Compound 2-11);-   (2-((1-(2,4-Difluorobenzyl)-3-methyl-1H-indol-4-yl)oxy)pyridin-4-yl)methanamine    (Compound 2-12);-   (2-((1-((6-Methoxypyridin-3-yl)methyl)-2-methyl-1H-indol-4-yl)oxy)pyridin-4-yl)methanamine    (Compound 2-13);-   (2-((1-((6-Methoxypyridin-3-yl)methyl)-3-methyl-1H-indol-4-yl)oxy)pyridin-4-yl)methanamine    (Compound 2-14);-   (2-((1-((5-Fluoropyridin-2-yl)methyl)-1H-indol-4-yl)oxy)pyridin-4-yl)    methanamine (Compound 2-15)-   (2-((1-(Quinolin-2-ylmethyl)-1H-indol-4-yl)oxy)pyridin-4-yl)methanamine    (Compound 2-16)-   (2-((1-((2-(Trifluoromethyl)thiazol-5-yl)methyl)-1H-indol-4-yl)oxy)pyridin-4-yl)methanamine    (Compound 2-17)-   (2-((1-(4-Fluorophenyl)-1H-indol-4-yl)oxy)pyridin-4-yl)methanamine    (Compound 2-18);-   (2-((1-(1-Methyl-1H-pyrazol-4-yl)-1H-indol-4-yl)oxy)pyridin-4-yl)methanamine    (Compound 2-19);-   (2-((1-(6-Methoxypyridin-3-yl)-1H-indol-4-yl)oxy)pyridin-4-yl)methanamine    (Compound 2-20);-   (2-((1-(6-Fluorobenzo[d]thiazol-2-yl)-1H-indol-4-yl)oxy)pyridin-4-yl)methanamine    (Compound 2-21);-   (2-((1-(4-Fluorophenethyl)-1H-indol-4-yl)oxy)pyridin-4-yl)methanamine    (Compound 2-22);-   (2-((3-Bromo-1-(4-fluorophenethyl)-1H-indol-4-yl)oxy)pyridin-4-yl)methanamine    (Compound 2-23);-   (4-((4-(Aminomethyl)pyridin-2-yl)oxy)-1H-indol-1-yl)(phenyl)methanone    (Compound 2-24);-   4-((4-(Aminomethyl)pyridin-2-yl)oxy)-N-phenyl-1H-indole-1-carboxamide    (Compound 2-25);-   2-(4-((4-(Aminomethyl)pyridin-2-yl)oxy)-1H-indol-1-yl)-N,N-dimethylacetamide    (Compound 2-26);-   2-(4-((4-(Aminomethyl)pyridin-2-yl)oxy)-1H-indol-1-yl)-1-(piperidin-1-yl)ethanone    (Compound 2-27);-   (R) or    (S)-2-(4-((4-(Aminomethyl)pyridin-2-yl)oxy)-1H-indol-1-yl)-1-(3-hydroxy-3-(trifluoromethyl)piperidin-1-yl)ethan-1-one    (Enantiomer 1) (Compound 2-28);-   (R) or    (S)-2-(4-((4-(Aminomethyl)pyridin-2-yl)oxy)-1H-indol-1-yl)-1-(3-hydroxy-3-(trifluoromethyl)piperidin-1-yl)ethan-1-one    (Enantiomer 2) (Compound 2-29);-   2-(4-((4-(Aminomethyl)pyridin-2-yl)oxy)-1H-indol-1-yl)-N-methyl-N-phenylacetamide    (Compound 2-30);-   2-(4-((4-(Aminomethyl)pyridin-2-yl)oxy)-1H-indol-1-yl)-1-(3,4-dihydroquinolin-1(2H)-yl)ethanone    (Compound 2-31);-   (2-((1H-Indol-4-yl)oxy)pyridin-4-yl)methanamine (Compound 2-32);-   (2-((1-(6-Fluorobenzo[d]thiazol-2-yl)indolin-4-yl)oxy)pyridin-4-yl)methanamine    (Compound 2-33);-   (2-((1-((6-Methoxypyridin-3-yl)methyl)-1H-indol-5-yl)oxy)pyridin-4-yl)methanamine    (Compound 2-34);-   (2-((1-(2,4-Difluorobenzyl)-3-methyl-1H-indazol-4-yl)oxy)pyridin-4-yl)methanamine    (Compound 2-35);-   5-((4-(Aminomethyl)pyridin-2-yl)oxy)-1-(2,4-difluorobenzyl)-3,4-dihydroquinolin-2(1H)-one    (Compound 2-36);-   5-((4-(Aminomethyl)pyridin-2-yl)oxy)-1-((6-methoxypyridin-3-yl)methyl)-3,4-dihydroquinolin-2(1H)-one    (Compound 2-37);-   (S)-(3-((4-(Aminomethyl)pyridin-2-yl)oxy)piperidin-1-yl)(phenyl)methanone    (Compound 2-38);-   (S)-3-((4-(Aminomethyl)pyridin-2-yl)oxy)-N-phenylpiperidine-1-carboxamide    (Compound 2-39);-   Racemic-(4-(aminomethyl)pyridin-2-yl)(3-hydroxy-3-(trifluoromethyl)pyrrolidin-1-yl)methanone    (Compound 2-40);-   4-(Aminomethyl)-N-benzylpicolinamide (Compound 2-41);-   N-(4-(Aminomethyl)pyridin-2-yl)-2-fluoro-4-methylbenzamide (Compound    2-42);-   N-(4-(Aminomethyl)pyridin-2-yl)-2-(3,4-dichlorophenyl)acetamide    (Compound 2-43);    or a pharmaceutically acceptable salt thereof.

TABLE 3

Compound Number R^(A) —L¹—

—L²—Q 3-1

O

3-2

O

3-3

O

In some embodiments, described herein is a compound that is:

-   4-(Aminomethyl)-N,N-dimethyl-6-(3-phenoxyphenoxy)pyridin-2-amine    (Compound 3-1);-   4-(Aminomethyl)-N-(2-methoxyethyl)-6-(3-phenoxyphenoxy)pyridin-2-amine    (Compound 3-2);-   (2-(4-Fluorophenyl)-6-(3-phenoxyphenoxy)pyridin-4-yl)methanamine    (Compound 3-3);    or a pharmaceutically acceptable salt thereof

TABLE 4

Compound Position Number R^(A) —CH₂NH₂ 4-1 2—F 3 4-2 3—F 4 4-3 2—F 4 4-42—CF₃ 4 4-5 2—Cl 4 4-6 2—OBn 4 4-7 2-O-c-hexyl 4 4-8 2-(4-fluorophenoxy)4 4-9 2-(2-trifluoromethylphenoxy) 4 4-10 2-(1-pyrrolidino) 4 4-112-(imidazol-1-yl) 4 4-12 2-(4-ethylpiperazin-1-yl) 4 4-132-((2-methoxyethyl)carbamoyl) 4 4-14 2-(3,3,3-trifluoropropanamido) 4

In some embodiments, described herein is a compound that is:

-   2-Fluoro-3-(aminomethyl)pyridine (Compound 4-1);-   3-Fluoro-4-(aminomethyl)pyridine (Compound 4-2);-   2-Fluoro-4-(aminomethyl)pyridine (Compound 4-3);-   2-Trifluoromethyl-4-(aminomethyl)pyridine (Compound 4-4);-   2-Chloro-4-(aminomethyl)pyridine (Compound 4-5);-   2-Benzyloxy-4-(aminomethyl)pyridine (Compound 4-6);-   2-Cyclohexyloxy-4-(aminomethyl)pyridine (Compound 4-7);-   2-(4-Fluorophenoxy)-4-(aminomethyl)pyridine (Compound 4-8);-   2-(2-Trifluoromethylphenoxy)-4-(aminomethyl)pyridine (Compound 4-9);-   2-(1-Pyrrolidino)-4-(aminomethyl)pyridine (Compound 4-10);-   2-(Imidazol-1-yl)-4-(aminomethyl)pyridine (Compound 4-11);-   2-(4-Ethylpiperazin-1-yl)-4-(aminomethyl)pyridine (Compound 4-12);-   4-(Aminomethyl)-N-(2-methoxyethyl)picolinamide (Compound 4-13);-   4-(Aminomethyl)-N-(2,2,2-trifluoroethyl)picolinamide (Compound    4-14);    or a pharmaceutically acceptable salt thereof.

Any combination of the groups described above for the various variablesis contemplated herein. Throughout the specification, groups andsubstituents thereof are chosen by one skilled in the field to providestable moieties and compounds.

In one aspect, compounds described herein are in the form ofpharmaceutically acceptable salts. As well, active metabolites of thesecompounds having the same type of activity are included in the scope ofthe present disclosure. In addition, the compounds described herein canexist in unsolvated as well as solvated forms with pharmaceuticallyacceptable solvents such as water, ethanol, and the like. The solvatedforms of the compounds presented herein are also considered to bedisclosed herein.

“Pharmaceutically acceptable,” as used herein, refers a material, suchas a carrier or diluent, which does not abrogate the biological activityor properties of the compound, and is relatively nontoxic, i.e., thematerial is administered to an individual without causing undesirablebiological effects or interacting in a deleterious manner with any ofthe components of the composition in which it is contained.

The term “pharmaceutically acceptable salt” refers to a form of atherapeutically active agent that consists of a cationic form of thetherapeutically active agent in combination with a suitable anion, or inalternative embodiments, an anionic form of the therapeutically activeagent in combination with a suitable cation. Handbook of PharmaceuticalSalts: Properties, Selection and Use. International Union of Pure andApplied Chemistry, Wiley-VCH 2002. S. M. Berge, L. D. Bighley, D. C.Monkhouse, J. Pharm. Sci. 1977, 66, 1-19. P. H. Stahl and C. G. Wermuth,editors, Handbook of Pharmaceutical Salts: Properties, Selection andUse, Weinheim/Zürich: Wiley-VCH/VHCA, 2002. Pharmaceutical saltstypically are more soluble and more rapidly soluble in stomach andintestinal juices than non-ionic species and so are useful in soliddosage forms. Furthermore, because their solubility often is a functionof pH, selective dissolution in one or another part of the digestivetract is possible and this capability can be manipulated as one aspectof delayed and sustained release behaviours. Also, because thesalt-forming molecule can be in equilibrium with a neutral form, passagethrough biological membranes can be adjusted.

In some embodiments, pharmaceutically acceptable salts are obtained byreacting a compound described herein with an acid. In some embodiments,the compound described herein (i.e. free base form) is basic and isreacted with an organic acid or an inorganic acid. Inorganic acidsinclude, but are not limited to, hydrochloric acid, hydrobromic acid,sulfuric acid, phosphoric acid, nitric acid, and metaphosphoric acid.Organic acids include, but are not limited to, 1-hydroxy-2-naphthoicacid; 2,2-dichloroacetic acid; 2-hydroxyethanesulfonic acid;2-oxoglutaric acid; 4-acetamidobenzoic acid; 4-aminosalicylic acid;acetic acid; adipic acid; ascorbic acid (L); aspartic acid (L);benzenesulfonic acid; benzoic acid; camphoric acid (+);camphor-10-sulfonic acid (+); capric acid (decanoic acid); caproic acid(hexanoic acid); caprylic acid (octanoic acid); carbonic acid; cinnamicacid; citric acid; cyclamic acid; dodecylsulfuric acid;ethane-1,2-disulfonic acid; ethanesulfonic acid; formic acid; fumaricacid; galactaric acid; gentisic acid; glucoheptonic acid (D); gluconicacid (D); glucuronic acid (D); glutamic acid; glutaric acid;glycerophosphoric acid; glycolic acid; hippuric acid; isobutyric acid;lactic acid (DL); lactobionic acid; lauric acid; maleic acid; malic acid(−L); malonic acid; mandelic acid (DL); methanesulfonic acid; monomethylfumarate, naphthalene-1,5-disulfonic acid; naphthalene-2-sulfonic acid;nicotinic acid; oleic acid; oxalic acid; palmitic acid; pamoic acid;phosphoric acid; proprionic acid; pyroglutamic acid (−L); salicylicacid; sebacic acid; stearic acid; succinic acid; sulfuric acid; tartaricacid (+L); thiocyanic acid; toluenesulfonic acid (p); and undecylenicacid.

In some embodiments, a compound described herein is prepared as achloride salt, sulfate salt, bromide salt, mesylate salt, maleate salt,citrate salt or phosphate salt. In some embodiments, a compounddescribed herein is prepared as a hydrochloride salt.

In some embodiments, pharmaceutically acceptable salts are obtained byreacting a compound described herein with a base. In some embodiments,the compound described herein is acidic and is reacted with a base. Insuch situations, an acidic proton of the compound described herein isreplaced by a metal ion, e.g., lithium, sodium, potassium, magnesium,calcium, or an aluminum ion. In some cases, compounds described hereincoordinate with an organic base, such as, but not limited to,ethanolamine, diethanolamine, triethanolamine, tromethamine, meglumine,N-methylglucamine, dicyclohexylamine, tris(hydroxymethyl)methylamine. Inother cases, compounds described herein form salts with amino acids suchas, but not limited to, arginine, lysine, and the like. Acceptableinorganic bases used to form salts with compounds that include an acidicproton, include, but are not limited to, aluminum hydroxide, calciumhydroxide, potassium hydroxide, sodium carbonate, potassium carbonate,sodium hydroxide, lithium hydroxide, and the like. In some embodiments,the compounds provided herein are prepared as a sodium salt, calciumsalt, potassium salt, magnesium salt, meglumine salt, N-methylglucaminesalt or ammonium salt. In some embodiments, the compounds providedherein are prepared as a sodium salt.

It should be understood that a reference to a pharmaceuticallyacceptable salt includes the solvent addition forms. In someembodiments, solvates contain either stoichiometric ornon-stoichiometric amounts of a solvent, and are formed during theprocess of crystallization with pharmaceutically acceptable solventssuch as water, ethanol, and the like. Hydrates are formed when thesolvent is water, or alcoholates are formed when the solvent is alcohol.Solvates of compounds described herein are conveniently prepared orformed during the processes described herein. In addition, the compoundsprovided herein optionally exist in unsolvated as well as solvatedforms.

The methods and formulations described herein include the use ofN-oxides (if appropriate), crystalline forms (also known as polymorphs),or pharmaceutically acceptable salts of compounds described herein, aswell as active metabolites of these compounds having the same type ofactivity.

In some embodiments, sites on the organic radicals (e.g. alkyl groups,aromatic rings) of compounds described herein are susceptible to variousmetabolic reactions. Incorporation of appropriate substituents on theorganic radicals will reduce, minimize or eliminate this metabolicpathway. In specific embodiments, the appropriate substituent todecrease or eliminate the susceptibility of the aromatic ring tometabolic reactions is, by way of example only, a halogen, deuterium, analkyl group, a haloalkyl group, or a deuteroalkyl group.

In another embodiment, the compounds described herein are labeledisotopically (e.g. with a radioisotope) or by another other means,including, but not limited to, the use of chromophores or fluorescentmoieties, bioluminescent labels, or chemiluminescent labels.

Compounds described herein include isotopically-labeled compounds, whichare identical to those recited in the various formulae and structurespresented herein, but for the fact that one or more atoms are replacedby an atom having an atomic mass or mass number different from theatomic mass or mass number usually found in nature. Examples of isotopesthat can be incorporated into the present compounds include isotopes ofhydrogen, carbon, nitrogen, oxygen, fluorine and chlorine, such as, forexample, ²H, ³H, ¹³C, ¹⁴C, ¹⁵N, ¹⁸O, ¹⁷O, ³⁵S, ¹⁸F, ³⁶Cl. In one aspect,isotopically-labeled compounds described herein, for example those intowhich radioactive isotopes such as ³H and ¹⁴C are incorporated, areuseful in drug and/or substrate tissue distribution assays. In oneaspect, substitution with isotopes such as deuterium affords certaintherapeutic advantages resulting from greater metabolic stability, suchas, for example, increased in vivo half-life or reduced dosagerequirements.

In some embodiments, the compounds described herein possess one or morestereocenters and each stereocenter exists independently in either the Ror S configuration. The compounds presented herein include alldiastereomeric, enantiomeric, atropisomers, and epimeric forms as wellas the appropriate mixtures thereof. The compounds and methods providedherein include all cis, trans, syn, anti, entgegen (E), and zusammen (Z)isomers as well as the appropriate mixtures thereof.

Individual stereoisomers are obtained, if desired, by methods such as,stereoselective synthesis and/or the separation of stereoisomers bychiral chromatographic columns. In certain embodiments, compoundsdescribed herein are prepared as their individual stereoisomers byreacting a racemic mixture of the compound with an optically activeresolving agent to form a pair of diastereoisomeric compounds/salts,separating the diastereomers and recovering the optically pureenantiomers. In some embodiments, resolution of enantiomers is carriedout using covalent diastereomeric derivatives of the compounds describedherein. In another embodiment, diastereomers are separated byseparation/resolution techniques based upon differences in solubility.In other embodiments, separation of steroisomers is performed bychromatography or by the forming diastereomeric salts and separation byrecrystallization, or chromatography, or any combination thereof. JeanJacques, Andre Collet, Samuel H. Wilen, “Enantiomers, Racemates andResolutions”, John Wiley And Sons, Inc., 1981. In some embodiments,stereoisomers are obtained by stereoselective synthesis.

In some embodiments, compounds described herein are prepared asprodrugs. A “prodrug” refers to an agent that is converted into theparent drug in vivo. Prodrugs are often useful because, in somesituations, they are easier to administer than the parent drug. Theyare, for instance, bioavailable by oral administration whereas theparent is not. The prodrug may be a substrate for a transporter. Furtheror alternatively, the prodrug also has improved solubility inpharmaceutical compositions over the parent drug. In some embodiments,the design of a prodrug increases the effective water solubility. Anexample, without limitation, of a prodrug is a compound describedherein, which is administered as an ester (the “prodrug”) but then ismetabolically hydrolyzed to provide the active entity. A further exampleof a prodrug is a short peptide (polyaminoacid) bonded to an acid groupwhere the peptide is metabolized to reveal the active moiety. In certainembodiments, upon in vivo administration, a prodrug is chemicallyconverted to the biologically, pharmaceutically or therapeuticallyactive form of the compound. In certain embodiments, a prodrug isenzymatically metabolized by one or more steps or processes to thebiologically, pharmaceutically or therapeutically active form of thecompound.

Prodrugs of the compounds described herein include, but are not limitedto, esters, ethers, carbonates, thiocarbonates, N-acyl derivatives,N-acyloxyalkyl derivatives, quaternary derivatives of tertiary amines,N-Mannich bases, Schiff bases, amino acid conjugates, phosphate esters,and sulfonate esters. See for example Design of Prodrugs, Bundgaard, A.Ed., Elseview, 1985 and Method in Enzymology, Widder, K. et al., Ed.;Academic, 1985, vol. 42, p. 309-396; Bundgaard, H. “Design andApplication of Prodrugs” in A Textbook of Drug Design and Development,Krosgaard-Larsen and H. Bundgaard, Ed., 1991, Chapter 5, p. 113-191; andBundgaard, H., Advanced Drug Delivery Review, 1992, 8, 1-38, each ofwhich is incorporated herein by reference. In some embodiments, ahydroxyl group in the compounds disclosed herein is used to form aprodrug, wherein the hydroxyl group is incorporated into an acyloxyalkylester, alkoxycarbonyloxyalkyl ester, alkyl ester, aryl ester, phosphateester, sugar ester, ether, and the like. In some embodiments, a hydroxylgroup in the compounds disclosed herein is a prodrug wherein thehydroxyl is then metabolized in vivo to provide a carboxylic acid group.In some embodiments, a carboxyl group is used to provide an ester oramide (i.e. the prodrug), which is then metabolized in vivo to provide acarboxylic acid group. In some embodiments, compounds described hereinare prepared as alkyl ester prodrugs.

Prodrug forms of the herein described compounds, wherein the prodrug ismetabolized in vivo to produce a compound described herein as set forthherein are included within the scope of the claims. In some cases, someof the herein-described compounds is a prodrug for another derivative oractive compound.

In additional or further embodiments, the compounds described herein aremetabolized upon administration to an organism in need to produce ametabolite that is then used to produce a desired effect, including adesired therapeutic effect.

A “metabolite” of a compound disclosed herein is a derivative of thatcompound that is formed when the compound is metabolized. The term“active metabolite” refers to a biologically active derivative of acompound that is formed when the compound is metabolized. The term“metabolized,” as used herein, refers to the sum of the processes(including, but not limited to, hydrolysis reactions and reactionscatalyzed by enzymes) by which a particular substance is changed by anorganism. Thus, enzymes may produce specific structural alterations to acompound. For example, cytochrome P450 catalyzes a variety of oxidativeand reductive reactions while uridine diphosphate glucuronyltransferasescatalyze the transfer of an activated glucuronic-acid molecule toaromatic alcohols, aliphatic alcohols, carboxylic acids, amines and freesulphydryl groups. Metabolites of the compounds disclosed herein areoptionally identified either by administration of compounds to a hostand analysis of tissue samples from the host, or by incubation ofcompounds with hepatic cells in vitro and analysis of the resultingcompounds.

Synthesis of Compounds

Compounds of Formula (I) described herein are synthesized using standardsynthetic techniques or using methods known in the art in combinationwith methods described herein.

Unless otherwise indicated, conventional methods of mass spectroscopy,NMR, HPLC, protein chemistry, biochemistry, recombinant DNA techniquesand pharmacology are employed.

Compounds are prepared using standard organic chemistry techniques suchas those described in, for example, March's Advanced Organic Chemistry,6^(th) Edition, John Wiley and Sons, Inc. Alternative reactionconditions for the synthetic transformations described herein may beemployed such as variation of solvent, reaction temperature, reactiontime, as well as different chemical reagents and other reactionconditions. The starting materials are available from commercial sourcesor are readily prepared.

Pyridines are prepared using well known synthetic routes (see Allais etal. Chem. Rev., 2014, 114, p 10829-10868 and references cited) and theseare further functionalized to provide 2-substituted pyridines using avariety of methods. In some embodiments, 2-chloropyridines are obtainedfrom direct chlorination of a pyridine using a suitable chlorinationreagent. In some embodiments, the chlorination reagent is Cl₂. In someembodiments, 2-chloropyridines are prepared from the treatment of2-hydroxypyridines with POCl₃. In other embodiments, 2-chloropyridinesare prepared by the chlorination of a pyridine-N-oxide with a suitablechlorination reagent. In some embodiments, the chlorination reagent isPOCl₃, phosgene, or triphosgene. 2-Aminopyridines are prepared by avariety of methods. In some embodiments, 2-aminopyridines are convertedto 2-halopyridines using the Sandmeyer reaction. In other embodiments,2-aminopyridines are prepared from the reaction of the correspondingN-oxide via treatment with t-butyl amine/Ts₂O followed by in situdeprotection (see Yin et al, J. Org. Chem., 2007, 72, p 4554-4557 andreferences cited).

In some embodiments, the O-linked compounds of Formula (I) having thegeneral structure 1-2 are prepared as shown in Scheme 1.

In some embodiments, 4-substituted-2-halo pyridine 1-1 is treated withan appropriately substituted alcohol R²OH in the presence of a strongbase using a suitable polar solvent to provide 1-2. In some embodiments,the strong base is KO^(t)Bu. In some embodiments, the polar solvent isDMF. In some embodiments, if R² is aryl or heteroaryl, a suitable milderbase may be employed. In some embodiments, the milder base is Cs₂CO₃. Inother embodiments, 1-2 is prepared from 2-hydroxypyridine (2-pyridone)1-3. In some embodiments, O-alkylation is performed with suitable baseand an alkylating agent in an appropriate organic solvent to provide1-2. In some embodiments, the suitable base is Ag₂CO₃. In otherembodiments, the suitable alkylating agent is R²—Br or R²—I. In otherembodiments, Mitsunobu conditions are used to achieve the sametransformation. In both cases the N-alkylated product may also beobtained.

In some embodiments, 2-thioalkylpyridines/2-thioarylpyridines areprepared as shown in Scheme 2.

In some embodiments, 2-thioalkylpyridines/2-thioarylpyridines 2-2(compounds of Formula (I) containing a sulfur linkage), are prepared bytreatment of the corresponding 2-halopyridine 2-1 with the appropriatethiol R²SH and a suitable base in a suitable solvent. In someembodiments, the suitable base is Cs₂CO₃. In some embodiments, thesuitable solvent is DMF.

In some embodiments, compounds of Formula (I) in which there is an aminelinking group (Y═NR²R^(2′)) are synthesized according to Scheme 3.

In some embodiments, nucleophilic displacement of a 2-halopyridine 3-1using an amine NHR²R^(2′) and a suitable base in a suitable organicsolvent provides 3-2. In some embodiments, heat and pressure facilitatethe reaction. In some embodiments, the suitable base is KO^(t)Bu. Insome embodiments, the suitable organic solvent is DMF. In someembodiments, a palladium or a copper catalyst is also used. In someembodiments, pyridines of general structure 3-3 are oxidized to theN-oxide (3-4) using a suitable oxidant. In some embodiments, thesuitable oxidant is mCPBA. In some embodiments, treatment of the N-oxidewith an amine NHR²R^(2′) in the presence ofbromotripyrrolidinophosphonium hexafluorophosphate (PyBroP) and asuitable organic base in a solvent yields 3-2 (see Londregan Org. Lett.,2010, 12, p 5254-5257). In some embodiments, the suitable organic baseis ^(i)PrEt₂N. In some embodiments, the suitable solvent is CH₂Cl₂.

In some embodiments, the compounds of Formula (I) containing an amidelinkage (4-4) are prepared as shown in Scheme 4.

In some embodiments, 2-halopyridine 4-1 is treated with CO in thepresence of a suitable palladium catalyst and a suitable base in asuitable organic solvent to afford ester 4-2. In some embodiments, thepalladium catalyst is PdCl₂(PPh₃)₄. In some embodiments, the base isNaOAc. In some embodiments, the organic solvent is MeOH. In someembodiments, the ester is hydrolyzed using aqueous LiOH with a suitableorganic solvent to afford acid 4-3. In some embodiments, the organicsolvent is MeOH or THF. In some embodiments, standard peptide couplingreaction conditions with an appropriately substituted amine HNR′R″ areused to yield amide 4-4.

In some embodiments, the compounds of Formula (I) containing amethyleneoxy or a methylene linkage are prepared as shown in Scheme 5.

In some embodiments, ester 5-1 is reduced to the alcohol 5-2 using asuitable reducing agent in an appropriate solvent. In some embodiments,the suitable reducing agent is NaBH₄. In some embodiments, theappropriate solvent is MeOH. In some embodiments, alcohol 5-2 isconverted to ether 5-3 using the Mitsunobu reaction protocol. In otherembodiments, alcohol 5-2 is converted into halogenated 5-4 using anappropriate halogenating reagent. In some embodiments, Y═Br in 5-4. Insome embodiments the halogenating reagent is TPP or CBr₄. In someembodiments, displacement of the leaving group on 5-4 with an alcohol orphenol is as described above yields 5-3. In other embodiments compound5-4 is reacted with other nucleophiles in the presence of a suitablebase and suitable solvent to provide the methylene linked compound 5-5.In some embodiments, the base is NaH. In some embodiments, the suitablesolvent is THF.

In some embodiments, the compounds of Formula (I) that contain a bond toan aryl (or heteroaryl) substituent are prepared as described in Scheme6.

In some embodiments, 2-halopyridine compound of general structure 6-1 isconverted to the corresponding 2-boronic acid or 2-boronate esterderivative 6-2 using standard methodologies, such as those described inLiu et al, ARKIVOC, 2013, (i) p 135-153. In some embodiments, a Suzukireaction employing 6-2 and an appropriately substituted aryl (orheteroaryl) bromide or iodide using a palladium catalyst in the presenceof a suitable base in a suitable solvent affords compound 6-3. In someembodiments, the palladium catalyst is Pd(OAc)₂ or Pd(PPh₃)₄). In otherembodiments, the suitable base is K₂CO₃. In other embodiments, thesolvent is DMF. In other embodiments, compound 6-1 is coupled with anaryl (or heteroaryl) boronic acid/ester using standard conditions forthe Suzuki reaction to afford 6-3 directly.

4-Aminomethylpyridines are prepared in a variety of ways. In someembodiments, 4-aminomethylpyridines are prepared as outline in Scheme 7.

In some embodiments, 4-bromo-2-picolinic ester derivative 7-1 isconverted to the 4-cyano analog 7-2 with Zn(CN)₂ in the presence of asuitable palladium catalyst. In some embodiments, the suitable palladiumcatalyst is Pd(PPh₃)₄. In some embodiments, reduction of the nitrilewith a suitable reducing agent affords the methyl amine 7-3. In someembodiments, the reducing agent is CoCl₂ and NaBH₄. In some embodiments,the use of NaBD₄ in place of NaBH₄ allows for the preparation of thecorresponding deuteromethyamine.

In some embodiments, pyridine compounds containing a 4-aminomethylsubstituent are prepared as shown in Scheme 8.

In some embodiments, the appropriately functionalized 4-aminomethylpyridine 8-1 is treated with Boc₂O to afford 8-2. In some embodiments,8-2 is transformed into 8-3 using the procedures described herein toinstall the appropriate substituent —ZR². In some embodiments,deprotection of the amine with TFA or HCl provides 8-4 as thecorresponding salt.

In some embodiments, the compounds of Formula (I) containing an amidelinkage (9-3) are prepared as shown in Scheme 9.

In some embodiments, 2-halopyridine 9-1 is treated with an amine NH₂R²in the presence of a suitable base and in an organic solvent to afford9-2. In some embodiments, the suitable base is KO^(t)Bu. In someembodiments, the suitable organic solvent is DMF. In some embodiments,standard peptide coupling reaction conditions with an appropriatelysubstituted carboxylic acid R³CO₂H affords amide 9-3.

2,6-Disubstituted pyridines are prepared in a variety of ways. In someembodiments, 2,6-disubstituted pyridines are prepared as shown in Scheme10.

In some embodiments, 2,6-dichloropyridine 10-1 is converted intoappropriately functionalized chloropyridine 10-2 using the proceduresdescribed herein and by carefully controlling amounts of reagentsemployed. In some embodiments, reaction of 10-2 with an aryl (orheteroaryl) boronic acid/ester using standard conditions for the Suzukireaction affords 10-3. In some embodiments, 10-2 is converted intoappropriately functionalized pyridines 10-4 using procedures describedherein.

In some embodiments, R^(A), as shown in any one of Schemes 1-10, ishydrogen.

In some embodiments, compounds are prepared as described in theExamples.

Certain Terminology

Unless otherwise stated, the following terms used in this applicationhave the definitions given below. The use of the term “including” aswell as other forms, such as “include”, “includes,” and “included,” isnot limiting. The section headings used herein are for organizationalpurposes only and are not to be construed as limiting the subject matterdescribed.

As used herein, C₁-C_(x) includes C₁-C₂, C₁-C₃ . . . C₁-C_(x). By way ofexample only, a group designated as “C₁-C₄” indicates that there are oneto four carbon atoms in the moiety, i.e. groups containing 1 carbonatom, 2 carbon atoms, 3 carbon atoms or 4 carbon atoms. Thus, by way ofexample only, “C₁-C₄ alkyl” indicates that there are one to four carbonatoms in the alkyl group, i.e., the alkyl group is selected from amongmethyl, ethyl, propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, andt-butyl.

An “alkyl” group refers to an aliphatic hydrocarbon group. The alkylgroup is branched or straight chain. In some embodiments, the “alkyl”group has 1 to 10 carbon atoms, i.e. a C₁-C₁₀alkyl. Whenever it appearsherein, a numerical range such as “1 to 10” refers to each integer inthe given range; e.g., “1 to 10 carbon atoms” means that the alkyl groupconsist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up toand including 10 carbon atoms, although the present definition alsocovers the occurrence of the term “alkyl” where no numerical range isdesignated. In some embodiments, an alkyl is a C₁-C₆alkyl. In one aspectthe alkyl is methyl, ethyl, propyl, iso-propyl, n-butyl, iso-butyl,sec-butyl, or t-butyl. Typical alkyl groups include, but are in no waylimited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl,sec-butyl, tertiary butyl, pentyl, neopentyl, or hexyl.

An “alkylene” group refers refers to a divalent alkyl radical. Any ofthe above mentioned monovalent alkyl groups may be an alkylene byabstraction of a second hydrogen atom from the alkyl. In someembodiments, an alkelene is a C₁-C₆alkylene. In other embodiments, analkylene is a C₁-C₄alkylene. Typical alkylene groups include, but arenot limited to, —CH₂—, —CH(CH₃)—, —C(CH₃)₂—, —CH₂CH₂—, —CH₂CH(CH₃)—,—CH₂C(CH₃)₂—, —CH₂CH₂CH₂—, —CH₂CH₂CH₂CH₂—, and the like.

“Deuteroalkyl” refers to an alkyl group where 1 or more hydrogen atomsof an alkyl are replaced with deuterium.

The term “alkenyl” refers to a type of alkyl group in which at least onecarbon-carbon double bond is present. In one embodiment, an alkenylgroup has the formula —C(R)═CR₂, wherein R refers to the remainingportions of the alkenyl group, which may be the same or different. Insome embodiments, R is H or an alkyl. Non-limiting examples of analkenyl group include —CH═CH₂, —C(CH₃)═CH₂, —CH═CHCH₃, —C(CH₃)═CHCH₃,and —CH₂CH═CH₂.

The term “alkynyl” refers to a type of alkyl group in which at least onecarbon-carbon triple bond is present. In one embodiment, an alkenylgroup has the formula —C≡C—R, wherein R refers to the remaining portionsof the alkynyl group. In some embodiments, R is H or an alkyl.Non-limiting examples of an alkynyl group include —C≡CH,—C≡CCH₃—C≡CCH₂CH₃, —CH₂C≡CH.

An “alkoxy” group refers to a (alkyl)O— group, where alkyl is as definedherein.

The term “alkylamine” refers to the —N(alkyl)_(x)H_(y) group, where x is0 and y is 2, or where x is 1 and y is 1, or where x is 2 and y is 0.

The term “aromatic” refers to a planar ring having a delocalizedit-electron system containing 4n+2 π electrons, where n is an integer.The term “aromatic” includes both carbocyclic aryl (“aryl”, e.g.,phenyl) and heterocyclic aryl (or “heteroaryl” or “heteroaromatic”)groups (e.g., pyridine). The term includes monocyclic or fused-ringpolycyclic (i.e., rings which share adjacent pairs of carbon atoms)groups.

The term “carbocyclic” or “carbocycle” refers to a ring or ring systemwhere the atoms forming the backbone of the ring are all carbon atoms.The term thus distinguishes carbocyclic from “heterocyclic” rings or“heterocycles” in which the ring backbone contains at least one atomwhich is different from carbon. In some embodiments, at least one of thetwo rings of a bicyclic carbocycle is aromatic. In some embodiments,both rings of a bicyclic carbocycle are aromatic. In some embodiments,bicyclic carbocycles are fused, bridged or spirocyclic.

As used herein, the term “aryl” refers to an aromatic ring wherein eachof the atoms forming the ring is a carbon atom. In one aspect, aryl isphenyl or a naphthyl. In some embodiments, an aryl is a phenyl. In someembodiments, an aryl is a C₆-C₁₀aryl. Depending on the structure, anaryl group is a monoradical or a diradical (i.e., an arylene group).

The term “cycloalkyl” refers to a monocyclic or polycyclic aliphatic,non-aromatic radical, wherein each of the atoms forming the ring (i.e.skeletal atoms) is a carbon atom. In some embodiments, cycloalkyls arespirocyclic or bridged compounds. In some embodiments, cycloalkyls areoptionally fused with an aromatic ring, and the point of attachment isat a carbon that is not an aromatic ring carbon atom. Cycloalkyl groupsinclude groups having from 3 to 10 ring atoms. In some embodiments,cycloalkyl groups are selected from among cyclopropyl, cyclobutyl,cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl,cyclooctyl, spiro[2.2]pentyl, norbornyl and bicycle[1.1.1]pentyl. Insome embodiments, a cycloalkyl is a C₃-C₆cycloalkyl.

The term “halo” or, alternatively, “halogen” or “halide” means fluoro,chloro, bromo or iodo. In some embodiments, halo is fluoro, chloro, orbromo.

The term “fluoroalkyl” refers to an alkyl in which one or more hydrogenatoms are replaced by a fluorine atom. In one aspect, a fluoralkyl is aC₁-C₆fluoroalkyl.

The term “heteroalkyl” refers to an alkyl group in which one or moreskeletal atoms of the alkyl are selected from an atom other than carbon,e.g., oxygen, nitrogen (e.g. —NH—, —N(alkyl)-, sulfur, or combinationsthereof. A heteroalkyl is attached to the rest of the molecule at acarbon atom of the heteroalkyl. In one aspect, a heteroalkyl is aC₁-C₆heteroalkyl.

The term “heterocycle” or “heterocyclic” refers to heteroaromatic rings(also known as heteroaryls) and heterocycloalkyl rings (also known asheteroalicyclic groups) containing one to four heteroatoms in thering(s), where each heteroatom in the ring(s) is selected from O, S andN, wherein each heterocyclic group has from 3 to 10 atoms in its ringsystem, and with the proviso that any ring does not contain two adjacentO or S atoms. Non-aromatic heterocyclic groups (also known asheterocycloalkyls) include rings having 3 to 10 atoms in its ring systemand aromatic heterocyclic groups include rings having 5 to 10 atoms inits ring system. The heterocyclic groups include benzo-fused ringsystems. Examples of non-aromatic heterocyclic groups are pyrrolidinyl,tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, oxazolidinonyl,tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, piperidinyl,morpholinyl, thiomorpholinyl, thioxanyl, piperazinyl, aziridinyl,azetidinyl, oxetanyl, thietanyl, homopiperidinyl, oxepanyl, thiepanyl,oxazepinyl, diazepinyl, thiazepinyl, 1,2,3,6-tetrahydropyridinyl,pyrrolin-2-yl, pyrrolin-3-yl, indolinyl, 2H-pyranyl, 4H-pyranyl,dioxanyl, 1,3-dioxolanyl, pyrazolinyl, dithianyl, dithiolanyl,dihydropyranyl, dihydrothienyl, dihydrofuranyl, pyrazolidinyl,imidazolinyl, imidazolidinyl, 3-azabicyclo[3.1.0]hexanyl,3-azabicyclo[4.1.0]heptanyl, 3H-indolyl, indolin-2-onyl,isoindolin-1-onyl, isoindoline-1,3-dionyl,3,4-dihydroisoquinolin-1(2H)-onyl, 3,4-dihydroquinolin-2(1H)-onyl,isoindoline-1,3-dithionyl, benzo[d]oxazol-2(3H)-onyl,1H-benzo[d]imidazol-2(3H)-onyl, benzo[d]thiazol-2(3H)-onyl, andquinolizinyl. Examples of aromatic heterocyclic groups are pyridinyl,imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl,furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl,quinolinyl, isoquinolinyl, indolyl, benzimidazolyl, benzofuranyl,cinnolinyl, indazolyl, indolizinyl, phthalazinyl, pyridazinyl,triazinyl, isoindolyl, pteridinyl, purinyl, oxadiazolyl, thiadiazolyl,furazanyl, benzofurazanyl, benzothiophenyl, benzothiazolyl,benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl, andfuropyridinyl. The foregoing groups are either C-attached (or C-linked)or N-attached where such is possible. For instance, a group derived frompyrrole includes both pyrrol-1-yl (N-attached) or pyrrol-3-yl(C-attached). Further, a group derived from imidazole includesimidazol-1-yl or imidazol-3-yl (both N-attached) or imidazol-2-yl,imidazol-4-yl or imidazol-5-yl (all C-attached). The heterocyclic groupsinclude benzo-fused ring systems. Non-aromatic heterocycles areoptionally substituted with one or two oxo (═O) moieties, such aspyrrolidin-2-one. In some embodiments, at least one of the two rings ofa bicyclic heterocycle is aromatic. In some embodiments, both rings of abicyclic heterocycle are aromatic. In some embodiments, bicyclicheterocycles are fused, bridged or spirocyclic.

The terms “heteroaryl” or, alternatively, “heteroaromatic” refers to anaryl group that includes one or more ring heteroatoms selected fromnitrogen, oxygen and sulfur. Illustrative examples of heteroaryl groupsinclude monocyclic heteroaryls and bicyclcic heteroaryls. Monocyclicheteroaryls include pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl,triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl,oxazolyl, isothiazolyl, pyrrolyl, pyridazinyl, triazinyl, oxadiazolyl,thiadiazolyl, and furazanyl. Monocyclic heteroaryls include indolizine,indole, benzofuran, benzothiophene, indazole, benzimidazole, purine,quinolizine, quinoline, isoquinoline, cinnoline, phthalazine,quinazoline, quinoxaline, 1,8-naphthyridine, and pteridine. In someembodiments, a heteroaryl contains 0-4 N atoms in the ring. In someembodiments, a heteroaryl contains 1-4 N atoms in the ring. In someembodiments, a heteroaryl contains 0-4 N atoms, 0-1 O atoms, and 0-1 Satoms in the ring. In some embodiments, a heteroaryl contains 1-4 Natoms, 0-1 O atoms, and 0-1 S atoms in the ring. In some embodiments,heteroaryl is a C₁-C₉heteroaryl. In some embodiments, monocyclicheteroaryl is a C₁-C₅heteroaryl. In some embodiments, monocyclicheteroaryl is a 5-membered or 6-membered heteroaryl. In someembodiments, bicyclic heteroaryl is a C₆-C₉heteroaryl.

A “heterocycloalkyl” or “heteroalicyclic” group refers to a cycloalkylgroup that includes at least one heteroatom selected from nitrogen,oxygen and sulfur. In some embodiments, a heterocycloalkyl is fused withan aryl or heteroaryl. In some embodiments, the heterocycloalkyl isoxazolidinonyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl,tetrahydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl,thiomorpholinyl, piperazinyl, piperidin-2-onyl,pyrrolidine-2,5-dithionyl, pyrrolidine-2,5-dionyl, pyrrolidinonyl,imidazolidinyl, imidazolidin-2-onyl, or thiazolidin-2-onyl. The termheteroalicyclic also includes all ring forms of the carbohydrates,including but not limited to the monosaccharides, the disaccharides andthe oligosaccharides. In one aspect, a heterocycloalkyl is aC₂-C₁₀heterocycloalkyl. In another aspect, a heterocycloalkyl is aC₄-C₁₀heterocycloalkyl. In some embodiments, a heterocycloalkyl contains0-2 N atoms in the ring. In some embodiments, a heterocycloalkylcontains 0-2 N atoms, 0-2 O atoms and 0-1 S atoms in the ring.

The term “bond” or “single bond” refers to a chemical bond between twoatoms, or two moieties when the atoms joined by the bond are consideredto be part of larger substructure. In one aspect, when a group describedherein is a bond, the referenced group is absent thereby allowing a bondto be formed between the remaining identified groups.

The term “moiety” refers to a specific segment or functional group of amolecule. Chemical moieties are often recognized chemical entitiesembedded in or appended to a molecule.

The term “optionally substituted” or “substituted” means that thereferenced group is optionally substituted with one or more additionalgroup(s) individually and independently selected from halogen, —CN,—NH₂, —NH(alkyl), —N(alkyl)₂, —OH, —CO₂H, —CO₂alkyl, —C(═O)NH₂,—C(═O)NH(alkyl), —C(═O)N(alkyl)₂, —S(═O)₂NH₂, —S(═O)₂NH(alkyl),—S(═O)₂N(alkyl)₂, alkyl, cycloalkyl, fluoroalkyl, heteroalkyl, alkoxy,fluoroalkoxy, heterocycloalkyl, aryl, heteroaryl, aryloxy, alkylthio,arylthio, alkylsulfoxide, arylsulfoxide, alkylsulfone, and arylsulfone.In some other embodiments, optional substituents are independentlyselected from halogen, —CN, —NH₂, —NH(CH₃), —N(CH₃)₂, —OH, —CO₂H,—CO₂(C₁-C₄alkyl), —C(═O)NH₂, —C(═O)NH(C₁-C₄alkyl), —C(═O)N(C₁-C₄alkyl)₂,—S(═O)₂NH₂, —S(═O)₂NH(C₁-C₄alkyl), —S(═O)₂N(C₁-C₄alkyl)₂, C₁-C₄alkyl,C₃-C₆cycloalkyl, C₁-C₄fluoroalkyl, C₁-C₄heteroalkyl, C₁-C₄alkoxy,C₁-C₄fluoroalkoxy, —SC₁-C₄alkyl, —S(═O)C₁-C₄alkyl, and—S(═O)₂C₁-C₄alkyl. In some embodiments, optional substituents areindependently selected from halogen, —CN, —NH₂, —OH, —NH(CH₃), —N(CH₃)₂,—CH₃, —CH₂CH₃, —CF₃, —OCH₃, and —OCF₃. In some embodiments, substitutedgroups are substituted with one or two of the preceding groups. In someembodiments, an optional substituent on an aliphatic carbon atom(acyclic or cyclic) includes oxo (═O).

The term “acceptable” with respect to a formulation, composition oringredient, as used herein, means having no persistent detrimentaleffect on the general health of the subject being treated.

The term “modulate” as used herein, means to interact with a targeteither directly or indirectly so as to alter the activity of the target,including, by way of example only, to enhance the activity of thetarget, to inhibit the activity of the target, to limit the activity ofthe target, or to extend the activity of the target.

The term “modulator” as used herein, refers to a molecule that interactswith a target either directly or indirectly. The interactions include,but are not limited to, the interactions of an agonist, partial agonist,an inverse agonist, antagonist, degrader, or combinations thereof. Insome embodiments, a modulator is an antagonist. In some embodiments, amodulator is a degrader.

The terms “administer,” “administering”, “administration,” and the like,as used herein, refer to the methods that may be used to enable deliveryof compounds or compositions to the desired site of biological action.These methods include, but are not limited to oral routes, intraduodenalroutes, parenteral injection (including intravenous, subcutaneous,intraperitoneal, intramuscular, intravascular or infusion), topical andrectal administration. Those of skill in the art are familiar withadministration techniques that can be employed with the compounds andmethods described herein. In some embodiments, the compounds andcompositions described herein are administered orally.

The terms “co-administration” or the like, as used herein, are meant toencompass administration of the selected therapeutic agents to a singlepatient, and are intended to include treatment regimens in which theagents are administered by the same or different route of administrationor at the same or different time.

The terms “effective amount” or “therapeutically effective amount,” asused herein, refer to a sufficient amount of an agent or a compoundbeing administered, which will relieve to some extent one or more of thesymptoms of the disease or condition being treated. The result includesreduction and/or alleviation of the signs, symptoms, or causes of adisease, or any other desired alteration of a biological system. Forexample, an “effective amount” for therapeutic uses is the amount of thecomposition comprising a compound as disclosed herein required toprovide a clinically significant decrease in disease symptoms. Anappropriate “effective” amount in any individual case is optionallydetermined using techniques, such as a dose escalation study.

The terms “enhance” or “enhancing,” as used herein, means to increase orprolong either in potency or duration a desired effect. Thus, in regardto enhancing the effect of therapeutic agents, the term “enhancing”refers to the ability to increase or prolong, either in potency orduration, the effect of other therapeutic agents on a system. An“enhancing-effective amount,” as used herein, refers to an amountadequate to enhance the effect of another therapeutic agent in a desiredsystem.

The term “pharmaceutical combination” as used herein, means a productthat results from the mixing or combining of more than one activeingredient and includes both fixed and non-fixed combinations of theactive ingredients. The term “fixed combination” means that the activeingredients, e.g. a compound described herein, or a pharmaceuticallyacceptable salt thereof, and a co-agent, are both administered to apatient simultaneously in the form of a single entity or dosage. Theterm “non-fixed combination” means that the active ingredients, e.g. acompound described herein, or a pharmaceutically acceptable saltthereof, and a co-agent, are administered to a patient as separateentities either simultaneously, concurrently or sequentially with nospecific intervening time limits, wherein such administration provideseffective levels of the two compounds in the body of the patient. Thelatter also applies to cocktail therapy, e.g. the administration ofthree or more active ingredients.

The terms “kit” and “article of manufacture” are used as synonyms.

The term “subject” or “patient” encompasses mammals. Examples of mammalsinclude, but are not limited to, any member of the Mammalian class:humans, non-human primates such as chimpanzees, and other apes andmonkey species; farm animals such as cattle, horses, sheep, goats,swine; domestic animals such as rabbits, dogs, and cats; laboratoryanimals including rodents, such as rats, mice and guinea pigs, and thelike. In one aspect, the mammal is a human.

The terms “treat,” “treating” or “treatment,” as used herein, includealleviating, abating or ameliorating at least one symptom of a diseaseor condition, preventing additional symptoms, inhibiting the disease orcondition, e.g., arresting the development of the disease or condition,relieving the disease or condition, causing regression of the disease orcondition, relieving a condition caused by the disease or condition, orstopping the symptoms of the disease or condition eitherprophylactically and/or therapeutically.

Pharmaceutical Compositions

In some embodiments, the compounds described herein are formulated intopharmaceutical compositions. Pharmaceutical compositions are formulatedin a conventional manner using one or more pharmaceutically acceptableinactive ingredients that facilitate processing of the active compoundsinto preparations that are used pharmaceutically. Proper formulation isdependent upon the route of administration chosen. A summary ofpharmaceutical compositions described herein is found, for example, inRemington: The Science and Practice of Pharmacy, Nineteenth Ed (Easton,Pa.: Mack Publishing Company, 1995); Hoover, John E., Remington'sPharmaceutical Sciences, Mack Publishing Co., Easton, Pa. 1975;Liberman, H. A. and Lachman, L., Eds., Pharmaceutical Dosage Forms,Marcel Decker, New York, N.Y., 1980; and Pharmaceutical Dosage Forms andDrug Delivery Systems, Seventh Ed. (Lippincott Williams & Wilkins 1999),herein incorporated by reference for such disclosure.

In some embodiments, the compounds described herein are administeredeither alone or in combination with pharmaceutically acceptablecarriers, excipients or diluents, in a pharmaceutical composition.Administration of the compounds and compositions described herein can beeffected by any method that enables delivery of the compounds to thesite of action. These methods include, though are not limited todelivery via enteral routes (including oral, gastric or duodenal feedingtube, rectal suppository and rectal enema), parenteral routes (injectionor infusion, including intraarterial, intracardiac, intradermal,intraduodenal, intramedullary, intramuscular, intraosseous,intraperitoneal, intrathecal, intravascular, intravenous, intravitreal,epidural and subcutaneous), inhalational, transdermal, transmucosal,sublingual, buccal and topical (including epicutaneous, dermal, enema,eye drops, ear drops, intranasal, vaginal) administration, although themost suitable route may depend upon for example the condition anddisorder of the recipient. By way of example only, compounds describedherein can be administered locally to the area in need of treatment, byfor example, local infusion during surgery, topical application such ascreams or ointments, injection, catheter, or implant. The administrationcan also be by direct injection at the site of a diseased tissue ororgan.

In some embodiments, pharmaceutical compositions suitable for oraladministration are presented as discrete units such as capsules, cachetsor tablets each containing a predetermined amount of the activeingredient; as a powder or granules; as a solution or a suspension in anaqueous liquid or a non-aqueous liquid; or as an oil-in-water liquidemulsion or a water-in-oil liquid emulsion. In some embodiments, theactive ingredient is presented as a bolus, electuary or paste.

Pharmaceutical compositions which can be used orally include tablets,push-fit capsules made of gelatin, as well as soft, sealed capsules madeof gelatin and a plasticizer, such as glycerol or sorbitol. Tablets maybe made by compression or molding, optionally with one or more accessoryingredients. Compressed tablets may be prepared by compressing in asuitable machine the active ingredient in a free-flowing form such as apowder or granules, optionally mixed with binders, inert diluents, orlubricating, surface active or dispersing agents. Molded tablets may bemade by molding in a suitable machine a mixture of the powdered compoundmoistened with an inert liquid diluent. In some embodiments, the tabletsare coated or scored and are formulated so as to provide slow orcontrolled release of the active ingredient therein. All formulationsfor oral administration should be in dosages suitable for suchadministration. The push-fit capsules can contain the active ingredientsin admixture with filler such as lactose, binders such as starches,and/or lubricants such as talc or magnesium stearate and, optionally,stabilizers. In soft capsules, the active compounds may be dissolved orsuspended in suitable liquids, such as fatty oils, liquid paraffin, orliquid polyethylene glycols. In some embodiments, stabilizers are added.Dragee cores are provided with suitable coatings. For this purpose,concentrated sugar solutions may be used, which may optionally containgum arabic, talc, polyvinyl pyrrolidone, carbopol gel, polyethyleneglycol, and/or titanium dioxide, lacquer solutions, and suitable organicsolvents or solvent mixtures. Dyestuffs or pigments may be added to thetablets or Dragee coatings for identification or to characterizedifferent combinations of active compound doses.

In some embodiments, pharmaceutical compositions are formulated forparenteral administration by injection, e.g., by bolus injection orcontinuous infusion. Formulations for injection may be presented in unitdosage form, e.g., in ampoules or in multi-dose containers, with anadded preservative. The compositions may take such forms as suspensions,solutions or emulsions in oily or aqueous vehicles, and may containformulatory agents such as suspending, stabilizing and/or dispersingagents. The compositions may be presented in unit-dose or multi-dosecontainers, for example sealed ampoules and vials, and may be stored inpowder form or in a freeze-dried (lyophilized) condition requiring onlythe addition of the sterile liquid carrier, for example, saline orsterile pyrogen-free water, immediately prior to use. Extemporaneousinjection solutions and suspensions may be prepared from sterilepowders, granules and tablets of the kind previously described.

Pharmaceutical compositions for parenteral administration includeaqueous and non-aqueous (oily) sterile injection solutions of the activecompounds which may contain antioxidants, buffers, bacteriostats andsolutes which render the formulation isotonic with the blood of theintended recipient; and aqueous and non-aqueous sterile suspensionswhich may include suspending agents and thickening agents. Suitablelipophilic solvents or vehicles include fatty oils such as sesame oil,or synthetic fatty acid esters, such as ethyl oleate or triglycerides,or liposomes. Aqueous injection suspensions may contain substances whichincrease the viscosity of the suspension, such as sodium carboxymethylcellulose, sorbitol, or dextran. Optionally, the suspension may alsocontain suitable stabilizers or agents which increase the solubility ofthe compounds to allow for the preparation of highly concentratedsolutions.

Pharmaceutical compositions may also be formulated as a depotpreparation. Such long acting formulations may be administered byimplantation (for example subcutaneously or intramuscularly) or byintramuscular injection. Thus, for example, the compounds may beformulated with suitable polymeric or hydrophobic materials (forexample, as an emulsion in an acceptable oil) or ion exchange resins, oras sparingly soluble derivatives, for example, as a sparingly solublesalt.

For buccal or sublingual administration, the compositions may take theform of tablets, lozenges, pastilles, or gels formulated in conventionalmanner. Such compositions may comprise the active ingredient in aflavored basis such as sucrose and acacia or tragacanth.

Pharmaceutical compositions may also be formulated in rectalcompositions such as suppositories or retention enemas, e.g., containingconventional suppository bases such as cocoa butter, polyethyleneglycol, or other glycerides.

Pharmaceutical compositions may be administered topically, that is bynon-systemic administration. This includes the application of a compoundof the present invention externally to the epidermis or the buccalcavity and the instillation of such a compound into the ear, eye andnose, such that the compound does not significantly enter the bloodstream. In contrast, systemic administration refers to oral,intravenous, intraperitoneal and intramuscular administration.

Pharmaceutical compositions suitable for topical administration includeliquid or semi-liquid preparations suitable for penetration through theskin to the site of inflammation such as gels, liniments, lotions,creams, ointments or pastes, and drops suitable for administration tothe eye, ear or nose. The active ingredient may comprise, for topicaladministration, from 0.001% to 10% w/w, for instance from 1% to 2% byweight of the formulation.

Pharmaceutical compositions for administration by inhalation areconveniently delivered from an insufflator, nebulizer pressurized packsor other convenient means of delivering an aerosol spray. Pressurizedpacks may comprise a suitable propellant such asdichlorodifluoromethane, trichlorofluoromethane,dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In thecase of a pressurized aerosol, the dosage unit may be determined byproviding a valve to deliver a metered amount. Alternatively, foradministration by inhalation or insufflation, pharmaceuticalpreparations may take the form of a dry powder composition, for examplea powder mix of the compound and a suitable powder base such as lactoseor starch. The powder composition may be presented in unit dosage form,in for example, capsules, cartridges, gelatin or blister packs fromwhich the powder may be administered with the aid of an inhalator orinsufflator.

It should be understood that in addition to the ingredients particularlymentioned above, the compounds and compositions described herein mayinclude other agents conventional in the art having regard to the typeof formulation in question, for example those suitable for oraladministration may include flavoring agents.

Methods of Dosing and Treatment Regimens

In one embodiment, the compounds described herein, or a pharmaceuticallyacceptable salt thereof, are used in the preparation of medicaments forthe treatment of diseases or conditions in a mammal that would benefitfrom inhibition or reduction of LOXL2 activity. Methods for treating anyof the diseases or conditions described herein in a mammal in need ofsuch treatment, involves administration of pharmaceutical compositionsthat include at least one compound described herein or apharmaceutically acceptable salt, active metabolite, prodrug, orpharmaceutically acceptable solvate thereof, in therapeuticallyeffective amounts to said mammal.

In certain embodiments, the compositions containing the compound(s)described herein are administered for prophylactic and/or therapeutictreatments. In certain therapeutic applications, the compositions areadministered to a patient already suffering from a disease or condition,in an amount sufficient to cure or at least partially arrest at leastone of the symptoms of the disease or condition. Amounts effective forthis use depend on the severity and course of the disease or condition,previous therapy, the patient's health status, weight, and response tothe drugs, and the judgment of the treating physician. Therapeuticallyeffective amounts are optionally determined by methods including, butnot limited to, a dose escalation and/or dose ranging clinical trial.

In prophylactic applications, compositions containing the compoundsdescribed herein are administered to a patient susceptible to orotherwise at risk of a particular disease, disorder or condition. Suchan amount is defined to be a “prophylactically effective amount ordose.” In this use, the precise amounts also depend on the patient'sstate of health, weight, and the like. When used in patients, effectiveamounts for this use will depend on the severity and course of thedisease, disorder or condition, previous therapy, the patient's healthstatus and response to the drugs, and the judgment of the treatingphysician. In one aspect, prophylactic treatments include administeringto a mammal, which previously experienced at least one symptom of thedisease being treated and is currently in remission, a pharmaceuticalcomposition comprising a compound described herein, or apharmaceutically acceptable salt thereof, in order to prevent a returnof the symptoms of the disease or condition.

In certain embodiments wherein the patient's condition does not improve,upon the doctor's discretion the administration of the compounds areadministered chronically, that is, for an extended period of time,including throughout the duration of the patient's life in order toameliorate or otherwise control or limit the symptoms of the patient'sdisease or condition.

In certain embodiments wherein a patient's status does improve, the doseof drug being administered is temporarily reduced or temporarilysuspended for a certain length of time (i.e., a “drug holiday”). Inspecific embodiments, the length of the drug holiday is between 2 daysand 1 year, including by way of example only, 2 days, 3 days, 4 days, 5days, 6 days, 7 days, 10 days, 12 days, 15 days, 20 days, 28 days, ormore than 28 days. The dose reduction during a drug holiday is, by wayof example only, by 10%-100%, including by way of example only 10%, 15%,20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%,90%, 95%, and 100%.

Once improvement of the patient's conditions has occurred, a maintenancedose is administered if necessary. Subsequently, in specificembodiments, the dosage or the frequency of administration, or both, isreduced, as a function of the symptoms, to a level at which the improveddisease, disorder or condition is retained. In certain embodiments,however, the patient requires intermittent treatment on a long-termbasis upon any recurrence of symptoms.

The amount of a given agent that corresponds to such an amount variesdepending upon factors such as the particular compound, diseasecondition and its severity, the identity (e.g., weight, sex) of thesubject or host in need of treatment, but nevertheless is determinedaccording to the particular circumstances surrounding the case,including, e.g., the specific agent being administered, the route ofadministration, the condition being treated, and the subject or hostbeing treated.

In general, however, doses employed for adult human treatment aretypically in the range of 0.01 mg-5000 mg per day. In one aspect, dosesemployed for adult human treatment are from about 1 mg to about 1000 mgper day. In one embodiment, the desired dose is conveniently presentedin a single dose or in divided doses administered simultaneously or atappropriate intervals, for example as two, three, four or more sub-dosesper day.

In one embodiment, the daily dosages appropriate for the compounddescribed herein, or a pharmaceutically acceptable salt thereof, arefrom about 0.01 to about 50 mg/kg per body weight. In some embodiments,the daily dosage or the amount of active in the dosage form are lower orhigher than the ranges indicated herein, based on a number of variablesin regard to an individual treatment regime. In various embodiments, thedaily and unit dosages are altered depending on a number of variablesincluding, but not limited to, the activity of the compound used, thedisease or condition to be treated, the mode of administration, therequirements of the individual subject, the severity of the disease orcondition being treated, and the judgment of the practitioner.

Toxicity and therapeutic efficacy of such therapeutic regimens aredetermined by standard pharmaceutical procedures in cell cultures orexperimental animals, including, but not limited to, the determinationof the LD₅₀ and the ED₅₀. The dose ratio between the toxic andtherapeutic effects is the therapeutic index and it is expressed as theratio between LD₅₀ and ED₅₀. In certain embodiments, the data obtainedfrom cell culture assays and animal studies are used in formulating thetherapeutically effective daily dosage range and/or the therapeuticallyeffective unit dosage amount for use in mammals, including humans. Insome embodiments, the daily dosage amount of the compounds describedherein lies within a range of circulating concentrations that includethe ED₅₀ with minimal toxicity. In certain embodiments, the daily dosagerange and/or the unit dosage amount varies within this range dependingupon the dosage form employed and the route of administration utilized.

In any of the aforementioned aspects are further embodiments in whichthe effective amount of the compound described herein, or apharmaceutically acceptable salt thereof, is: (a) systemicallyadministered to the mammal; and/or (b) administered orally to themammal; and/or (c) intravenously administered to the mammal; and/or (d)administered by injection to the mammal; and/or (e) administeredtopically to the mammal; and/or (f) administered non-systemically orlocally to the mammal.

In any of the aforementioned aspects are further embodiments comprisingsingle administrations of the effective amount of the compound,including further embodiments in which (i) the compound is administeredonce a day; or (ii) the compound is administered to the mammal multipletimes over the span of one day.

In any of the aforementioned aspects are further embodiments comprisingmultiple administrations of the effective amount of the compound,including further embodiments in which (i) the compound is administeredcontinuously or intermittently: as in a single dose; (ii) the timebetween multiple administrations is every 6 hours; (iii) the compound isadministered to the mammal every 8 hours; (iv) the compound isadministered to the mammal every 12 hours; (v) the compound isadministered to the mammal every 24 hours. In further or alternativeembodiments, the method comprises a drug holiday, wherein theadministration of the compound is temporarily suspended or the dose ofthe compound being administered is temporarily reduced; at the end ofthe drug holiday, dosing of the compound is resumed. In one embodiment,the length of the drug holiday varies from 2 days to 1 year.

In certain instances, it is appropriate to administer at least onecompound described herein, or a pharmaceutically acceptable saltthereof, in combination with one or more other therapeutic agents. Incertain embodiments, the pharmaceutical composition further comprisesone or more anti-cancer agents.

In one embodiment, the therapeutic effectiveness of one of the compoundsdescribed herein is enhanced by administration of an adjuvant (i.e., byitself the adjuvant has minimal therapeutic benefit, but in combinationwith another therapeutic agent, the overall therapeutic benefit to thepatient is enhanced). Or, in some embodiments, the benefit experiencedby a patient is increased by administering one of the compoundsdescribed herein with another agent (which also includes a therapeuticregimen) that also has therapeutic benefit.

In one specific embodiment, a compound described herein, or apharmaceutically acceptable salt thereof, is co-administered with asecond therapeutic agent, wherein the compound described herein, or apharmaceutically acceptable salt thereof, and the second therapeuticagent modulate different aspects of the disease, disorder or conditionbeing treated, thereby providing a greater overall benefit thanadministration of either therapeutic agent alone.

In any case, regardless of the disease, disorder or condition beingtreated, the overall benefit experienced by the patient may be additiveof the two therapeutic agents or the patient may experience asynergistic benefit.

In certain embodiments, different therapeutically-effective dosages ofthe compounds disclosed herein will be utilized in formulatingpharmaceutical composition and/or in treatment regimens when thecompounds disclosed herein are administered in combination with one ormore additional agent, such as an additional therapeutically effectivedrug, an adjuvant or the like. Therapeutically-effective dosages ofdrugs and other agents for use in combination treatment regimens isoptionally determined by means similar to those set forth hereinabovefor the actives themselves. Furthermore, the methods ofprevention/treatment described herein encompasses the use of metronomicdosing, i.e., providing more frequent, lower doses in order to minimizetoxic side effects. In some embodiments, a combination treatment regimenencompasses treatment regimens in which administration of a compounddescribed herein, or a pharmaceutically acceptable salt thereof, isinitiated prior to, during, or after treatment with a second agentdescribed herein, and continues until any time during treatment with thesecond agent or after termination of treatment with the second agent. Italso includes treatments in which a compound described herein, or apharmaceutically acceptable salt thereof, and the second agent beingused in combination are administered simultaneously or at differenttimes and/or at decreasing or increasing intervals during the treatmentperiod. Combination treatment further includes periodic treatments thatstart and stop at various times to assist with the clinical managementof the patient.

It is understood that the dosage regimen to treat, prevent, orameliorate the condition(s) for which relief is sought, is modified inaccordance with a variety of factors (e.g. the disease, disorder orcondition from which the subject suffers; the age, weight, sex, diet,and medical condition of the subject). Thus, in some instances, thedosage regimen actually employed varies and, in some embodiments,deviates from the dosage regimens set forth herein.

For combination therapies described herein, dosages of theco-administered compounds vary depending on the type of co-drugemployed, on the specific drug employed, on the disease or conditionbeing treated and so forth. In additional embodiments, whenco-administered with one or more other therapeutic agents, the compoundprovided herein is administered either simultaneously with the one ormore other therapeutic agents, or sequentially.

In combination therapies, the multiple therapeutic agents (one of whichis one of the compounds described herein) are administered in any orderor even simultaneously. If administration is simultaneous, the multipletherapeutic agents are, by way of example only, provided in a single,unified form, or in multiple forms (e.g., as a single pill or as twoseparate pills).

The compounds described herein, or a pharmaceutically acceptable saltthereof, as well as combination therapies, are administered before,during or after the occurrence of a disease or condition, and the timingof administering the composition containing a compound varies. Thus, inone embodiment, the compounds described herein are used as aprophylactic and are administered continuously to subjects with apropensity to develop conditions or diseases in order to prevent theoccurrence of the disease or condition. In another embodiment, thecompounds and compositions are administered to a subject during or assoon as possible after the onset of the symptoms. In specificembodiments, a compound described herein is administered as soon as ispracticable after the onset of a disease or condition is detected orsuspected, and for a length of time necessary for the treatment of thedisease. In some embodiments, the length required for treatment varies,and the treatment length is adjusted to suit the specific needs of eachsubject. For example, in specific embodiments, a compound describedherein or a formulation containing the compound is administered for atleast 2 weeks, about 1 month to about 5 years.

In some embodiments, a compound described herein, or a pharmaceuticallyacceptable salt thereof, is administered in combination withchemotherapy, hormone blocking therapy, radiation therapy, monoclonalantibodies, or combinations thereof.

Chemotherapy includes the use of anti-cancer agents.

In one aspect, the compound described herein, or a pharmaceuticallyacceptable salt thereof, is administered or formulated in combinationwith one or more anti-cancer agents.

Examples

The following examples are provided for illustrative purposes only andnot to limit the scope of the claims provided herein.

Synthesis of Int-A

Step 1: Ethyl 4-(4-cyanopyridin-2-yl)benzoate (A-2)

A stirred solution of 2-chloro-4-pyridinecarbonitrile A-1 (1.0 g, 7.22mmol), 4-ethoxycarbonylphenylboronic acid (1.68 g, 8.66 mmol), aq. 2MNa₂CO₃ (4 mL, 8.0 mmol) and MeCN (12 mL), was purged with a stream ofnitrogen for 10 min at RT. To the mixture was added Pd(dppf)Cl₂. DCM(264 mg, 0.36 mmol). The mixture was sealed and heated at 100° C. for 45min. After cooling to RT, the mixture was diluted with MeCN (50 mL) andthe obtained solid was collected via filtration and dried to affordcompound A-2 as a white solid (1.43 g, 79%) which did not requirefurther purification. ¹H NMR (300 MHz, DMSO-d₆): δ 8.94 (m, 1H), 8.58(s, 1H), 8.28-8.31 (m, 2H), 8.06-8.10 (m, 2H), 7.88 (m, 1H), 4.30-4.40(m, 2H), 1.25-1.40 (m, 3H); LCMS Mass: 253.0 (M⁺+1).

Step 2: Ethyl 4-(4-(aminomethyl)pyridin-2-yl)benzoate (A-3)

A mixture of nitrile A-2 (1.43 g, 5.67 mmol), 10 wt % Pd/C (0.28 mmol, 5mol %) and EtOAc: MeOH (1:1, 100 mL), was stirred under H₂ gas (1atmosphere pressure) at RT for 16 h. The mixture was filtered throughcelite and the celite washed with additional MeOH (100 mL). The combinedfiltrates were concentrated under reduced pressure to afford compoundA-3 as an oil (1.14 g, 79%). ¹H NMR (300 MHz, DMSO-d₆): δ 8.58 (m, 1H),8.21-8.24 (m, 2H), 8.02-8.06 (m, 3H), 7.36 (m, 1H), 4.25-4.35 (m, 2H),4.11 (br s, 2H), 3.15 (s, 2H), 1.25-1.40 (m, 3H); LCMS Mass: 257.0(M⁺+1).

Step 3: Ethyl4-(4-(((tert-butoxycarbonyl)amino)methyl)pyridin-2-yl)benzoate (A-4)

To a stirred solution of amine A-3 (1.14 g, 4.45 mmol) in a mixture ofTHF: DCM (2:1, 30 mL) at RT, was added di-tert-butyl dicarbonate (1.46g, 6.67 mmol) and DIEA (1.44 g, 11.13 mmol). The mixture was stirred atRT for 15 min. The mixture partitioned between DCM (100 mL) and aq. 0.5MHCl (50 mL). The organic layer was separated, dried over MgSO₄,filtered, and concentrated under reduced pressure. The residue waspurified (silica gel; 0-70% EtOAc in hexanes) to afford compound A-4 asa solid (1.42 g, 78%). ¹H NMR (300 MHz, DMSO-d₆): δ 8.62 (m, 1H),8.17-8.20 (m, 2H), 8.05-8.08 (m, 2H), 7.89 (m, 1H), 7.55 (m, 1H), 7.25(m, 1H), 4.20-4.40 (m, 2H), 4.15-4.30 (m, 2H), 1.26-1.40 (m, 12H); LCMSMass: 357.0 (M⁺+1).

Step 4: 4-(4-(((tert-Butoxycarbonyl)amino)methyl)pyridin-2-yl)benzoicAcid (Int-A)

To a stirred solution of ester A-4 (805 mg, 2.26 mmol) in THF (17 mL) atRT, was added aq. 2M LiOH (12 mL, 24 mmol) and the mixture stirred at RTfor 72 h. The mixture was cooled to 0° C., neutralized with aq. 2M HCl,then acidified to pH 3-4 using aq. sat. citric acid. The mixture waspartitioned between EtOAc (60 mL) and water (20 mL). The organic layerwas separated and the aq. layer was re-extracted with EtOAc (30 mL). Thecombined organic layers were dried (Na₂SO₄), filtered, and concentratedunder reduced pressure to afford Int-A as a white solid (741 mg, 100%)which did not require further purification. ¹H NMR (300 MHz, DMSO-d₆): δ8.61 (m, 1H), 8.10-8.16 (m, 2H), 8.00-8.06 (m, 2H), 7.87 (m, 1H), 7.56(m, 1H), 7.22 (m, 1H), 4.20-4.25 (m, 2H), 1.41 (s, 9H); LCMS Mass: 329.0(M⁺+1).

Synthesis of Int-B

3-(4-(((tert-Butoxycarbonyl)amino)methyl)pyridin-2-yl)benzoic Acid(Int-B)

The title compound (Int-B) was prepared using the procedure describedfor Int-A, using 3-methoxycarbonylphenylboronic acid pinacol ester inStep 1. ¹H NMR (300 MHz, DMSO-d₆): δ 12.99 (s, 1H), 8.59-8.62 (m, 2H),8.28 (m, 1H), 7.99 (m, 1H), 7.86 (m, 1H), 7.55-7.65 (m, 2H), 7.23 (m,1H), 4.22-4.24 (m, 2H), 1.40 (s, 9H); LCMS Mass: 329.0 (M⁺+1).

Synthesis of Int-C

Step 1: Methyl 4-((4-cyanopyridin-2-yl)oxy)benzoate (C-2)

To a solution of 2-chloro-4-pyridinecarbonitrile C-1 (1.0 g, 7.22 mmol)and methyl 4-hydroxybenzoate (1.10 g, 7.22 mmol) in DMA (10 ml), wasadded Cs₂CO₃ (3.53 g, 10.83 mmol). The reaction mixture was heated at80° C. for 1 h. After cooling to RT, the mixture was partitioned betweenwater (200 mL) and EtOAc (100 mL). The organic layer was separated andthe aqueous layer was re-extracted with EtOAc (1×100 ml). The combinedorganic layers were dried (MgSO₄), filtered, and then concentrated underreduced pressure. The crude residue was purified (silica gel; elutingwith 0-60% EtOAc in hexanes), to afford compound C-2 as a solid (1.07 g,58%). ¹H NMR (300 MHz, DMSO-d₆): δ 8.39 (m, 1H), 7.99-8.03 (m, 2H), 7.74(m, 1H), 7.63 (m, 1H), 7.28-7.32 (m, 2H), 3.84 (s, 3H); LCMS Mass: 255.0(M⁺+1).

Step 2: Methyl 4-((4-(aminomethyl)pyridin-2-yl)oxy)benzoate (C-3)

The title compound (C-3) (1.09 g, 100%) was prepared from methyl4-((4-cyanopyridin-2-yl)oxy)benzoate (C-2), using the proceduredescribed for compound A-3 (see Int-A Step 2). ¹H NMR (300 MHz,DMSO-d₆): δ 8.08 (m, 1H), 7.96-8.00 (m, 2H), 7.15-7.22 (m, 3H), 7.10 (m,1H), 3.83 (s, 3H), 3.78 (s, 2H); LCMS Mass: 259.0 (M⁺+1).

Step 3: Methyl4-((4-(((tert-butoxycarbonyl)amino)methyl)pyridin-2-yl)oxy)benzoate(C-4)

The title compound (C-4) (1.01 g, 67%) was prepared from methyl4-((4-(aminomethyl)pyridin-2-yl)oxy)benzoate (C-3), using the proceduredescribed for compound A-4 (see Step 3 of Int-A synthesis). ¹H NMR (300MHz, DMSO-d₆): δ 8.10 (m, 1H), 7.96-8.00 (m, 2H), 7.52 (m, 1H),7.19-7.22 (m, 2H), 7.04 (m, 1H), 6.89 (m, 1H), 4.15-4.18 (m, 2H), 3.84(s, 3H), 1.37 (s, 9H); LCMS Mass: 359.0 (M⁺+1).

Step 4:4-((4-(((tert-Butoxycarbonyl)amino)methyl)pyridin-2-yl)oxy)benzoic Acid(Int-C)

The title compound (Int-C) (800 mg, 83%) was prepared from methyl4-((4-(((tert-butoxycarbonyl)amino)methyl)pyridin-2-yl)oxy)benzoate(C-4), using the procedure described for compound Int-A (see Int-A Step4). LCMS Mass: 345.0 (M⁺+1).

Synthesis of Int-D

3-((4-(((tert-Butoxycarbonyl)amino)methyl)pyridin-2-yl)oxy)benzoic Acid(Int-D)

The title compound (Int-D) was prepared using the procedure describedfor Int-C, using methyl 3-hydroxybenzoate in Step 1. ¹H NMR (300 MHz,DMSO-d₆): δ 12.99 (s, 1H), 8.06 (m, 1H), 7.76 (m, 1H), 7.50-7.60 (m,3H), 7.37 (m, 1H), 7.00 (m, 1H), 6.86 (m, 1H), 4.15-4.17 (m, 2H), 1.37(s, 9H); LCMS Mass: 345.0 (M⁺+1).

Synthesis of Int-E

3-(((4-(((tert-Butoxycarbonyl)amino)methyl)pyridin-2-yl)oxy)methyl)benzoicAcid (Int-E)

The title compound (Int-E) was prepared using the procedure describedfor Int-C, using 3-(hydroxymethyl)-benzoic acid methyl ester in Step 1.¹H NMR (300 MHz, DMSO-d₆): δ 13.00 (br s, 1H), 8.06 (m, 1H), 7.98 (m,1H), 7.86 (m, 1H), 7.66 (m, 1H), 7.43-7.54 (m, 2H), 6.85 (m, 1H), 6.70(m, 1H), 5.40 (s, 2H), 4.08-4.15 (m, 2H), 1.37 (s, 9H); LCMS Mass: 359.0(M⁺+1).

Example 1: 4-(4-(Aminomethyl)pyridin-2-yl)-N-(2-methoxyethyl)benzamideHydrochloride (Compound 1-1)

Step 1: tert-Butyl((2-(4-((2-methoxyethyl)carbamoyl)phenyl)pyridin-4-yl)methyl) Carbamate(1)

To a stirred solution of Int-A (80 mg, 0.244 mmol) in DCM (2 mL), wasadded HATU (139 mg, 0.364 mmol) and the mixture was stirred at RT for 10min. 2-Methoxyethylamine (27 mg, 0.365 mmol) and DIEA (110 mg, 0.854mmol) were added and the mixture stirred at RT for 20 h. The DCM wasevaporated under reduced pressure and the remaining reaction mixture waspartitioned between water (20 mL) and EtOAc (20 mL). The organic layerwas separated, dried (Na₂SO₄), filtered, and then concentrated underreduced pressure. The crude residue was purified (silica gel; elutingwith 0-100% EtOAc in hexanes), to afford compound 1 as a white solid (94mg, 100%). ¹H NMR (300 MHz, DMSO-d₆): δ 8.58-8.63 (m, 2H), 8.10-8.15 (m,2H), 7.94-7.98 (m, 2H), 7.87 (m, 1H), 7.54 (m, 1H), 7.22 (m, 1H),4.19-4.24 (m, 2H), 3.40-3.50 (m, 4H), 3.26 (s, 3H), 1.40 (s, 9H); LCMSMass: 386.0 (M⁺+1).

Step 2: 4-(4-(Aminomethyl)pyridin-2-yl)-N-(2-methoxyethyl)benzamideHydrochloride (Compound 1-1)

To a stirred mixture of amide 1 (94 mg, 0.244 mmol) in DCM (2 mL) at RT,was added 2M HCl in Et₂O (2.0 mL, 4.0 mmol). The mixture was stirred atRT for 18 h. The mixture was concentrated under reduced pressure toafford the title compound 1-1 (73 mg, 94%) as a white solid. ¹H NMR (300MHz, DMSO-d₆): δ 8.63-8.75 (br m, 5H), 8.27 (m, 1H), 8.15-8.21 (m, 2H),7.97-8.02 (m, 2H), 7.52 (m, 1H), 4.10-4.20 (m, 2H), 3.40-3.50 (m, 4H),3.26 (s, 3H); LCMS Mass: 286.0 (M⁺+1).

Example 2:Racemic-(4-(4-(aminomethyl)pyridin-2-yl)phenyl)(3-hydroxy-3-(trifluoromethyl)pyrrolidin-1-yl)methanoneHydrochloride (Compound 1-2)

The title compound (1-2) was prepared using the procedure for Example 1,using racemic-3-(trifluoromethyl)pyrrolidin-3-ol hydrochloride inStep 1. LCMS Mass: 366.0 (M⁺+1).

Example 3: 4-(4-(Aminomethyl)pyridin-2-yl)-N-phenylbenzamideHydrochloride (Compound 1-3)

The title compound (1-3) was prepared using the procedure for Example 1,using aniline in Step 1. LCMS Mass: 304.0 (M⁺+1).

Example 4: 4-(4-(Aminomethyl)pyridin-2-yl)-N-benzylbenzamideHydrochloride (Compound 1-4)

The title compound (1-4) was prepared using the procedure for Example 1,using benzylamine in Step 1. LCMS Mass: 318.0 (M⁺+1).

Example 5: 3-(4-(Aminomethyl)pyridin-2-yl)-N-(2-methoxyethyl)benzamideHydrochloride (Compound 1-5)

The title compound (1-5) was prepared using the procedure for Example 1,using Int-B in Step 1. LCMS Mass: 286.0 (M⁺+1).

Example 6:Racemic-(3-(4-(aminomethyl)pyridin-2-yl)phenyl)(3-hydroxy-3-(trifluoromethyl)pyrrolidin-1-yl)methanoneHydrochloride (Compound 1-6)

The title compound (1-6) was prepared using the procedure for Example 1,using Int-B and racemic-3-(trifluoromethyl)pyrrolidin-3-ol hydrochloridein Step 1. LCMS Mass: 366.0 (M⁺+1).

Example 7: 3-(4-(Aminomethyl)pyridin-2-yl)-N-phenylbenzamideHydrochloride (Compound 1-7)

The title compound (1-7) was prepared using the procedure for Example 1,using Int-B and aniline in Step 1. LCMS Mass: 304.0 (M⁺+1).

Example 8: 3-(4-(Aminomethyl)pyridin-2-yl)-N-benzylbenzamideHydrochloride (Compound 1-8)

The title compound (1-8) was prepared using the procedure for Example 1,using Int-B and benzylamine in Step 1. LCMS Mass: 318.0 (M⁺+1).

Example 9:3-(4-(Aminomethyl)pyridin-2-yl)-N-(5-chloro-2-methylphenyl)benzamideHydrochloride (Compound 1-9)

The title compound (1-9) was prepared using the procedure for Example 1,using Int-B and 5-chloro-2-methylaniline in Step 1. LCMS Mass: 352.0(M⁺+1).

Example 10:3-(4-(Aminomethyl)pyridin-2-yl)-N-(6-chloro-1H-indol-4-yl)benzamideHydrochloride (Compound 1-10)

The title compound (1-10) was prepared using the procedure for Example1, using Int-B and 6-chloro-1H-indol-4-amine in Step 1. LCMS Mass: 377.0(M⁺+1).

Example 11:4-((4-(Aminomethyl)pyridin-2-yl)oxy)-N-(2-methoxyethyl)benzamideHydrochloride (Compound 1-11)

The title compound (1-11) was prepared using the procedure for Example1, using Int-C in Step 1. LCMS Mass: 302.0 (M⁺+1).

Example 12:Racemic-4-((4-(aminomethyl)pyridin-2-yl)oxy)phenyl)(3-hydroxy-3-(trifluoromethyl)pyrrolidin-1-yl)methanoneHydrochloride (Compound 1-12)

The title compound (1-12) was prepared using the procedure for Example1, using Int-C and racemic-3-(trifluoromethyl)pyrrolidin-3-olhydrochloride in Step 1. LCMS Mass: 382.0 (M⁺+1).

Example 13: 4-((4-(Aminomethyl)pyridin-2-yl)oxy)-N-phenylbenzamideHydrochloride (Compound 1-13)

The title compound (1-13) was prepared using the procedure for Example1, using Int-C and aniline in Step 1. LCMS Mass: 320.0 (M⁺+1).

Example 14: 4-((4-(Aminomethyl)pyridin-2-yl)oxy)-N-benzylbenzamideHydrochloride (Compound 1-14)

The title compound (1-14) was prepared using the procedure for Example1, using Int-C and benzylamine in Step 1. LCMS Mass: 334.0 (M⁺+1).

Example 15:3-((4-(Aminomethyl)pyridin-2-yl)oxy)-N-(2-methoxyethyl)benzamideHydrochloride (Compound 1-15)

The title compound (1-15) was prepared using the procedure for Example1, using Int-D in Step 1. LCMS Mass: 302.0 (M⁺+1).

Example 16:Racemic-(3-((4-(aminomethyl)pyridin-2-yl)oxy)phenyl)(3-hydroxy-3-(trifluoromethyl)pyrrolidin-1-yl)methanoneHydrochloride (Compound 1-16)

The title compound (1-16) was prepared using the procedure for Example1, using Int-D and racemic-3-(trifluoromethyl)pyrrolidin-3-olhydrochloride in Step 1. LCMS Mass: 382.0 (M⁺+1).

Example 17: 3-((4-(Aminomethyl)pyridin-2-yl)oxy)-N-phenylbenzamideHydrochloride (Compound 1-17)

The title compound (1-17) was prepared using the procedure for Example1, using Int-D and aniline in Step 1. LCMS Mass: 320.0 (M⁺+1).

Example 18: 3-((4-(Aminomethyl)pyridin-2-yl)oxy)-N-benzylbenzamideHydrochloride (Compound 1-18)

The title compound (1-18) was prepared using the procedure for Example1, using Int-D and benzylamine in Step 1. LCMS Mass: 334.0 (M⁺+1).

Example 19:3-((4-(Aminomethyl)pyridin-2-yl)oxy)-N-(3-methoxyphenyl)benzamideHydrochloride (Compound 1-19)

The title compound (1-19) was prepared using the procedure for Example1, using Int-D and 3-methoxyaniline in Step 1. LCMS Mass: 350.0 (M⁺+1).

Example 20:3-((4-(Aminomethyl)pyridin-2-yl)oxy)-N-(4-methoxyphenyl)benzamideHydrochloride (Compound 1-20)

The title compound (1-20) was prepared using the procedure for Example1, using Int-D and 4-methoxyaniline in Step 1. LCMS Mass: 350.0 (M⁺+1).

Example 21:3-((4-(Aminomethyl)pyridin-2-yl)oxy)-N-(3-(trifluoromethyl)phenyl)benzamideHydrochloride (Compound 1-21)

The title compound (1-21) was prepared using the procedure for Example1, using Int-D and 3-(trifluoromethyl)aniline in Step 1. LCMS Mass:388.0 (M⁺+1).

Example 22:3-((4-(Aminomethyl)pyridin-2-yl)oxy)-N-(4-(trifluoromethyl)phenyl)benzamideHydrochloride (Compound 1-22)

The title compound (1-22) was prepared using the procedure for Example1, using Int-D and 4-(trifluoromethyl)aniline in Step 1. LCMS Mass:388.0 (M⁺+1).

Example 23:3-((4-(Aminomethyl)pyridin-2-yl)oxy)-N-(4-fluorophenyl)benzamideHydrochloride (Compound 1-23)

The title compound (1-23) was prepared using the procedure for Example1, using Int-D and 4-fluoroaniline in Step 1. LCMS Mass: 338.0 (M⁺+1).

Example 24:3-((4-(Aminomethyl)pyridin-2-yl)oxy)-N-(2,4-difluorophenyl)benzamideHydrochloride (Compound 1-24)

The title compound (1-24) was prepared using the procedure for Example1, using Int-D and 2,4-difluoroaniline in Step 1. LCMS Mass: 356.0(M⁺+1).

Example 25:3-((4-(Aminomethyl)pyridin-2-yl)oxy)-N-(4-bromophenyl)benzamideHydrochloride (Compound 1-25)

The title compound (1-25) was prepared using the procedure for Example1, using Int-D and 4-bromoaniline in Step 1. LCMS Mass: 398.0 and 400.0(M⁺+1) (Br isotopic pattern).

Example 26: Methyl4-(3-((4-(aminomethyl)pyridin-2-yl)oxy)benzamido)benzoate Hydrochloride(Compound 1-26)

The title compound (1-26) was prepared using the procedure for Example1, using Int-D and methyl-4-aminobenzoate in Step 1. LCMS Mass: 378.0(M⁺+1).

Example 27: Ethyl3-(3-((4-(aminomethyl)pyridin-2-yl)oxy)benzamido)benzoate Hydrochloride(Compound 1-27)

The title compound (1-27) was prepared using the procedure for Example1, using Int-D and ethyl-3-aminobenzoate in Step 1. LCMS Mass: 392.0(M⁺+1).

Example 28: 3-(3-((4-(Aminomethyl)pyridin-2-yl)oxy)benzamido)benzoicAcid Hydrochloride (Compound 1-28)

Step 1: Ethyl3-(3-((4-(((tert-butoxycarbonyl)amino)methyl)pyridin-2-yl)oxy)benzamido)benzoate(1)

To a stirred solution of Int-D (200 mg, 0.58 mmol) in DMF (4 mL), wasadded HATU (442 mg, 1.16 mmol) and the mixture was stirred at RT for 20min. Ethyl-3-aminobenzoate (144 mg, 0.87 mmol) and DIEA (224 mg, 1.74mmol) were added and the mixture stirred at RT for 20 h. The reactionmixture was diluted with water (15 mL) and brine (1 mL), and the mixtureextracted with EtOAc (3×10 mL). The combined organic layers were dried(MgSO₄), filtered, and then concentrated under reduced pressure. Thecrude residue was purified (silica gel; eluting with 0-80% EtOAc inhexanes), to afford compound 1 as a yellow oil (155 mg, 54%). ¹H NMR(300 MHz, DMSO-d₆): δ 10.46 (s, 1H), 8.40 (m, 1H), 8.03-8.10 (m, 2H),7.85 (m, 1H), 7.67-7.76 (m, 2H), 7.46-7.62 (m, 3H), 7.37 (m, 1H), 7.02(m, 1H), 6.87 (m, 1H), 4.28-4.35 (m, 2H), 4.14-4.20 (m, 2H), 1.38 (s,9H), 1.30-1.37 (m, 3H); LCMS Mass: 514.0 (M⁺+Na).

Step 2:3-(3-((4-(((tert-Butoxycarbonyl)amino)methyl)pyridin-2-yl)oxy)benzamido)benzoicAcid (2)

To a stirred solution of ester 1 (111 mg, 0.226 mmol) in THF (1.5 mL) atRT, was added aq. 2M LiOH (1.5 mL, 3.0 mmol) and the mixture stirred atRT for 16 h. The mixture was diluted with water (4 mL), then acidifiedto pH 3-4 using aq. sat. citric acid. The mixture was extracted withEtOAc (2×30 mL) and the combined organic layers were dried (MgSO₄),filtered, and concentrated under reduced pressure. The crude residue waspurified (silica gel; eluting with 0-100% EtOAc in hexanes), to affordcompound 2 as a white solid (69 mg, 68%). ¹H NMR (300 MHz, DMSO-d₆): δ12.99 (s, 1H), 10.43 (s, 1H), 8.39 (m, 1H), 8.00-8.10 (m, 2H), 7.85 (m,1H), 7.74 (m, 1H), 7.68 (m, 1H), 7.42-7.62 (m, 3H), 7.35 (m, 1H), 7.02(m, 1H), 6.87 (m, 1H), 4.15-4.25 (m, 2H), 1.38 (s, 9H); LCMS Mass: 486.0(M⁺+Na).

Step 3: 3-(3-((4-(Aminomethyl)pyridin-2-yl)oxy)benzamido)benzoic AcidHydrochloride (Compound 1-28)

The title compound (1-28) was obtained from3-(3-((4-(((tert-butoxycarbonyl)amino)methyl)pyridin-2-yl)oxy)benzamido)benzoic acid (2) (48 mg, 89%) using theprocedure described in Example 1, Step 2. ¹H NMR (300 MHz, DMSO-d₆): δ10.49 (s, 1H), 8.56 (br s, 3H), 8.40 (m, 1H), 8.19 (m, 1H), 8.04 (m,1H), 7.87 (m, 1H), 7.56-7.73 (m, 3H), 7.46 (m, 1H), 7.38 (m, 1H),7.24-7.30 (m, 2H), 4.09-4.16 (m, 2H); LCMS Mass: 364.0 (M⁺+1).

Example 29: 4-(3-((4-(Aminomethyl)pyridin-2-yl)oxy)benzamido)benzoicAcid Hydrochloride (Compound 1-29)

The title compound (1-29) was prepared using the procedure for Example28, using methyl-4-aminobenzoate in Step 1. LCMS Mass: 364.0 (M⁺+1).

Example 30:3-((4-(Aminomethyl)pyridin-2-yl)oxy)-N-(2,4-difluorobenzyl)benzamideHydrochloride (Compound 1-30)

The title compound (1-30) was prepared using the procedure for Example1, using Int-D and 2,4-difluorobenzylamine in Step 1. LCMS Mass: 370.0(M⁺+1).

Example 31:3-((4-(Aminomethyl)pyridin-2-yl)oxy)-N-(4-(trifluoromethyl)benzyl)benzamideHydrochloride (Compound 1-31)

The title compound (1-31) was prepared using the procedure for Example1, using Int-D and 4-(trifluoromethyl)benzylamine in Step 1. LCMS Mass:402.0 (M⁺+1).

Example 32:3-((4-(Aminomethyl)pyridin-2-yl)oxy)-N-(4-bromobenzyl)benzamideHydrochloride (Compound 1-32)

The title compound (1-32) was prepared using the procedure for Example1, using Int-D and 4-bromobenzylamine in Step 1. LCMS Mass: 412.0 and414.0 (M⁺+1) (Br isotopic pattern).

Example 33: Methyl4-((3-((4-(aminomethyl)pyridin-2-yl)oxy)benzamido)methyl)benzoateHydrochloride (Compound 1-33)

The title compound (1-33) was prepared using the procedure for Example1, using Int-D and methyl-4-(aminomethyl)benzoate hydrochloride inStep 1. LCMS Mass: 392.0 (M⁺+1).

Example 34:4-((3-((4-(Aminomethyl)pyridin-2-yl)oxy)benzamido)methyl)benzoic acidHydrochloride (Compound 1-34)

The title compound (1-34) was prepared using the procedure for Example28, using methyl-4-(aminomethyl)benzoate in Step 1. LCMS Mass: 378.0(M⁺+1).

Example 35:3-((3-((4-(Aminomethyl)pyridin-2-yl)oxy)benzamido)methyl)benzoic acidHydrochloride (Compound 1-35)

The title compound (1-35) was prepared using the procedure for Example28, using methyl-3-(aminomethyl)benzoate in Step 1. ¹H NMR (300 MHz,DMSO-d₆): δ 9.23 (m, 1H), 8.59 (br s, 3H), 8.17 (m, 1H), 7.88 (m, 1H),7.75-7.83 (m, 2H), 7.61 (m, 1H), 7.50-7.58 (m, 2H), 7.43 (m, 1H), 7.31(m, 1H), 7.22-7.28 (m, 2H), 4.47-4.52 (m, 2H), 4.05-4.15 (m, 2H); LCMSMass: 378.0 (M⁺+1).

Example 36:(R)-3-((4-(Aminomethyl)pyridin-2-yl)oxy)-N-(2-hydroxy-1-phenylethyl)benzamideHydrochloride (Compound 1-36)

The title compound (1-36) was prepared using the procedure for Example1, using Int-D and (R)-(−)-2-phenylglycinol in Step 1. LCMS Mass: 364.0(M⁺+1).

Example 37:3-((4-(Aminomethyl)pyridin-2-yl)oxy)-N-(3-fluoro-4-(1H-imidazol-1-yl)benzyl)benzamideDihydrochloride (Compound 1-37)

The title compound (1-37) was prepared using the procedure for Example1, using Int-D and [3-fluoro-4-(1H-imidazol-1-yl)phenyl]methylamine inStep 1. ¹H NMR (300 MHz, DMSO-d₆): δ 9.58 (s, 1H), 9.41 (m, 1H), 8.69(br s, 3H), 8.12-8.17 (m, 2H), 7.93 (m, 1H), 7.26-7.81 (m, 2H), 7.64 (m,1H), 7.50-7.56 (m, 2H), 7.40 (m, 1H), 7.25-7.33 (m, 3H), 4.52-4.54 (m,2H), 4.07-4.13 (m, 2H); LCMS Mass: 418.0 (M⁺+1).

Example 38:3-((4-(Aminomethyl)pyridin-2-yl)oxy)-N-(4-(4-ethylpiperazin-1-yl)benzyl)benzamideDihydrochloride (Compound 1-38)

The title compound (1-38) was prepared using the procedure for Example1, using Int-D and 4-(4-ethylpiperazin-1-ylmethyl)benzylamine in Step 1.¹H NMR (300 MHz, DMSO-d₆): δ 9.23 (m, 1H), 8.58 (br s, 3H), 8.16 (m,1H), 7.78 (m, 1H), 7.50-7.63 (m, 4H), 7.22-7.39 (m, 5H), 4.46-4.48 (m,2H), 4.35 (s, 2H), 4.00-4.11 (m, 2H), 3.05-3.70 (m, 10H), 1.19-1.24 (m,3H); LCMS Mass: 460.0 (M⁺+1).

Example 39:3-((4-(Aminomethyl)pyridin-2-yl)oxy)-N-(3-carbamimidoylbenzyl)benzamideDihydrochloride (Compound 1-39)

The title compound (1-39) was prepared using the procedure for Example1, using Int-D and 3-aminomethylbenzamidine dihydrochloride in Step 1.¹H NMR (300 MHz, DMSO-d₆): δ 9.35 (m, 1H), 8.78 (br s, 3H), 8.49 (m,1H), 8.14 (m, 1H), 7.70-7.82 (m, 3H), 7.64 (m, 1H), 7.46-7.58 (m, 3H),7.26-7.32 (m, 3H), 4.49-4.51 (m, 2H), 4.05-4.15 (m, 2H); LCMS Mass:376.0 (M⁺+1).

Example 40: 3-((4-(Aminomethyl)pyridin-2-yl)oxy)-N-phenethylbenzamideHydrochloride (Compound 1-40)

The title compound (1-40) was prepared using the procedure for Example1, using Int-D and 2-phenethylamine in Step 1. LCMS Mass: 348.0 (M⁺+1).

Example 41:(3-((4-(Aminomethyl)pyridin-2-yl)oxy)phenyl))(3,4-dihydroisoquinolin-2(1H)-yl)methanoneTrifluoroacetate (Compound 1-41)

The title compound (1-41) was prepared using the procedure for Example1, using Int-D and 1,2,3,4-tetrahydroisoquinoline in Step 1. LCMS Mass:360.0 (M⁺+1).

Example 42:3-((4-(Aminomethyl)pyridin-2-yl)oxy)-N-(benzo[b]thiophen-2-ylmethyl)benzamideHydrochloride (Compound 1-42)

The title compound (1-42) was prepared using the procedure for Example1, using Int-D and 1-benzothiophen-2-ylmethylamine in Step 1. LCMS Mass:390.0 (M⁺+1).

Example 43:3-((4-(Aminomethyl)pyridin-2-yl)oxy)-N-(pyrazin-2-ylmethyl)benzamideHydrochloride (Compound 1-43)

The title compound (1-43) was prepared using the procedure for Example1, using Int-D and 2-(aminomethyl)pyrazine in Step 1. LCMS Mass: 336.0(M⁺+1).

Example 44: 3-((4-(Aminomethyl)pyridin-2-yl)oxy)-N-tridecylbenzamideHydrochloride (Compound 1-44)

The title compound (1-44) was prepared using the procedure for Example1, using Int-D and tridecylamine in Step 1. LCMS Mass: 426.0 (M⁺+1).

Example 45:3-(((4-(Aminomethyl)pyridin-2-yl)oxy)methyl)-N-phenylbenzamideHydrochloride (Compound 1-45)

The title compound (1-45) was prepared using the procedure for Example1, using Int-E and aniline in Step 1. LCMS Mass: 334.0 (M⁺+1).

Example 46: (2-((1-Benzyl-1H-indol-4-yl)oxy)pyridin-4-yl)methanamineHydrochloride (Compound 2-10)

Step 1: 4-(Benzyloxy)-1H-indole (2)

To a stirred solution of 1H-indol-4-ol 1 (3.2 g, 12.9 mmol) in DMF (17mL) at RT, were added benzyl bromide (2.43 g, 14.2 mmol) and K₂CO₃ (5.35g, 38.7 mmol). The reaction mixture was stirred at RT for 1.5 h.Additional benzyl bromide (0.40 g, 2.33 mmol) was added and the mixturestirred at RT for 30 min. The mixture was diluted with water (200 mL)and extracted with EtOAc (3×50 mL). The combined organic extracts werewashed with brine (20 mL), dried (Na₂SO₄), filtered, and concentratedunder reduced pressure. The crude was purified (silica gel; eluting0-60% EtOAc/hexanes) to afford compound 2 as an amber oil (2.88 g,100%). ¹H NMR (500 MHz, DMSO-d₆): δ 11.08 (s, 1H), 7.20-7.55 (m, 5H),6.93-7.10 (m, 3H), 6.58 (m, 1H), 6.48 (m, 1H), 5.19 (s, 2H).

Step 2: 1-Benzyl-4-(benzyloxy)-1H-indole (3)

To a stirred solution of compound 2 (250 mg, 1.12 mmol) in DMF (2 mL) atRT were added NaH (56 mg of a 60% dispersion in mineral oil, 1.40 mmol).The mixture was stirred at RT for 15 min, before cooling to 0° C. Asolution of benzyl bromide (210 mg, 1.23 mmol) in DMF (0.7 mL) was addedand the mixture warmed to RT and stirred for 2 h. The mixture wasconcentrated under reduced pressure, then partitioned between water (50mL) and EtOAc (25 mL). The organic layer was separated, dried (Na₂SO₄),filtered, and concentrated under reduced pressure. The crude waspurified (silica gel; eluting 0-60% EtOAc/hexanes) to afford compound 3as a white solid (302 mg, 86%). LCMS Mass: 314.0 (M⁺+1).

Step 3: 1-Benzyl-1H-indol-4-ol (4)

To a stirred solution of compound 3 (302 mg, 0.96 mmol) in EtOAc (10 mL)and MeOH (7 mL) was added 10% Pd/C (10% wt %, 5 mol %) under inertatmosphere. The reaction mixture was evacuated and stirred under H₂atmosphere (balloon) at RT for 4 h. The reaction mixture was filteredthrough a pad of celite and washed with EtOAc (10 mL). The filtrate wasconcentrated under reduced pressure and the residue purified (silicagel; eluting 0-100% EtOAc/hexanes) to afford compound 4 as a white solid(214 mg, 100%). LCMS Mass: 224.0 (M⁺+1).

Step 4: 2-((1-Benzyl-1H-indol-4-yl)oxy)isonicotinonitrile (5)

To a stirred solution of 2-chloropyridine-4-carbonitrile (29 mg, 0.210mmol) and compound 4 (50 mg, 0.210 mmol) in THF: DMF (1:1, 3 mL) at RT,was added Cs₂CO₃ (205 mg, 0.63 mmol). The mixture was stirred at 60° C.for 4 h. Additional 2-chloropyridine-4-carbonitrile (10 mg, 0.07 mmol)was added and the mixture stirred at 40° C. for 60 h. The mixture wasconcentrated under reduced pressure, and the residue purified (silicagel; eluting 0-100% EtOAc/hexanes) to afford compound 5 as an orange oil(52 mg, 73%). LCMS Mass: 326.0 (M⁺+1).

Step 5: (2-((1-Benzyl-1H-indol-4-yl)oxy)pyridin-4-yl)methanamineHydrochloride (Compound 2-10)

To a stirred solution of compound 5 (52 mg, 0.160 mmol) in a mixture ofEtOAc (1.5 mL) and HOAc (1 mL) was added 10% Pd/C (10% wt %, 5 mol %).The reaction mixture was evacuated and stirred under H₂ atmosphere(balloon) at RT for 3.5 h. Additional 10% Pd/C (10% wt %, 5 mol %) wasadded and the mixture stirred under H₂ atmosphere (balloon) for afurther 1.5 h. The reaction mixture was filtered through a pad of celiteand washed with EtOAc (10 mL). The filtrate was concentrated underreduced pressure and the residue purified via HPLC (Waters XTerra® PrepMS C-18 OBD 5 μM 50×100 mm column; eluting with 10-90% ACN/H₂Ocontaining 0.1% TFA, over 20 min) to afford(2-((1-benzyl-1H-indol-4-yl)oxy)pyridin-4-yl)methanamine as atrifluoroacetate salt. This salt was dissolved in a mixture of water andEtOAc and basified with aq. sat. NaHCO₃. The mixture was extracted withEtOAc and the organic layer separated, dried (Na₂SO₄), filtered, andconcentrated under reduced pressure. The residue was dissolved in THF (1mL) and to this was added 2M HCl in ether (1 mL). The mixture wasstirred at RT for 30 min. Concentration under reduced pressure affordedcompound 2-10 as a light yellow solid (29 mg, 50%). ¹H NMR (500 MHz,DMSO-d₆): δ 8.32 (br s, 3H), 8.10 (m, 1H), 7.45 (m, 1H), 7.15-7.38 (m,8H), 7.09 (m, 1H), 6.74 (m, 1H), 6.10 (m, 1H), 5.42 (s, 2H), 4.06 (s,2H); LCMS Mass: 330.0 (M⁺+1).

Example 47:(2-((1-((5-Fluoropyridin-2-yl)methyl)-1H-indol-4-yl)oxy)pyridin-4-yl)methanamine Hydrochloride (Compound 2-15)

Step 1: 2-((1H-Indol-4-yl)oxy)isonicotinonitrile (2)

To a stirred solution of 1H-indol-4-ol 1 (1 g, 7.52 mmol) in DMF (10 mL)were added 2-chloroisonicotinonitrile (0.52 g, 3.76 mmol) and K₂CO₃ (1.5g, 11.28 mmol). The reaction mixture was heated in a microwavesynthesizer at 150° C. for 30 min. The reaction mixture was cooled toRT, diluted with water (40 mL), then extracted with Et₂O (2×60 mL). Thecombined organic extracts were washed with brine (20 mL), dried(Na₂SO₄), filtered, and concentrated under reduced pressure. The cruderesidue was purified (silica gel; eluting 20% EtOAc/hexanes) to affordcompound 2 as a pale brown solid (250 mg, 14%). ¹H NMR (400 MHz,DMSO-d₆): δ 11.30 (br s, 1H), 8.32 (dd, J=5.1, 0.7 Hz, 1H), 7.58-7.56(m, 1H), 7.53 (dd, J=5.1, 1.3 Hz, 1H), 7.33-7.28 (m, 2H), 7.11 (t, J=7.9Hz, 1H), 6.79 (d, J=7.6 Hz, 1H), 6.08-6.05 (m, 1H); LCMS Mass: 235.9(M⁺+1).

Step 2: 2-(Chloromethyl)-5-fluoropyridine (3)

To a stirred solution of (5-fluoropyridin-2-yl) methanol 5 (500 mg, 3.94mmol) in CH₂Cl₂ (40 mL) at RT under an inert atmosphere, was added SOCl₂(0.43 mL, 5.9 mmol) drop wise and the mixture stirred for 1 h. Thereaction mixture was quenched with saturated NaHCO₃ (40 mL) andextracted with CH₂Cl₂ (2×50 mL). The combined organic extracts werewashed with water (20 mL), brine (20 mL), dried (Na₂SO₄), filtered, andconcentrated under reduced pressure to afford compound 3 (620 mg) aspale brown viscous liquid. This material was used without purification.

Step 3:2-((1-((5-Fluoropyridin-2-yl)methyl)-1H-indol-4-yl)oxy)isonicotinonitrile(4)

To a stirred solution of compound 2 (100 mg, 0.42 mmol) in DMF (5 mL) atRT under an inert atmosphere, were added2-(chloromethyl)-5-fluoropyridine 3 (92 mg, 0.64 mmol), Cs₂CO₃ (276 mg,0.85 mmol) and nBu₄NBr (cat.). The mixture was stirred at RT for 12 h.The reaction mixture was quenched with water (20 mL) and extracted withEtOAc (2×30 mL). The combined organic extracts were washed with brine(15 mL), dried (Na₂SO₄), filtered, and concentrated under reducedpressure. The residue was purified (silica gel; eluting 10%EtOAc/hexanes) to afford compound 4 as an off-white solid (110 mg, 75%).¹H NMR (500 MHz, DMSO-d₆): δ 8.53 (d, J=2.9 Hz, 1H), 8.30 (d, J=4.9 Hz,1H), 7.69 (td, J=8.7, 2.9 Hz, 1H), 7.62 (s, 1H), 7.54 (dd, J=5.1, 1.0Hz, 1H), 7.45 (d, J=2.9 Hz, 1H), 7.37 (d, J=8.1 Hz, 1H), 7.25 (dd,J=8.7, 4.3 Hz, 1H), 7.12 (t, J=8.0 Hz, 1H), 6.82 (d, J=7.5 Hz, 1H), 6.15(d, J=2.6 Hz, 1H), 5.52 (s, 2H); LCMS Mass: 345.0 (M⁺+1).

Step 4: (2-((1-((5-Fluoropyridin-2-yl)methyl)-1H-indol-4-yl)oxy)pyridin-4-yl)methanamine Hydrochloride (Compound 2-15)

To a stirred solution of compound 4 (110 mg, 0.32 mmol) in THF/MeOH(1:1, 10 mL) at 0° C. were added CoCl₂ (82 mg, 0.64 mmol) and NaBH₄ (121mg, 3.2 mmol) portion wise. The mixture was warmed to RT and stirred for3 h. The reaction mixture was filtered through a pad of celite and theresidue was washed with EtOAc (10 mL). The filtrate was concentratedunder reduced pressure. The residue was diluted with water (20 mL) andextracted with EtOAc (2×30 mL). The organic layer was separated, dried(Na₂SO₄), filtered, and concentrated under reduced pressure to affordthe desired amine.

To this amine was added 2M HCl in Et₂O (10 mL) at 0° C. and the mixturestirred for 30 min. Concentration under reduced pressure followed bytrituration with Et₂O (2×5 mL) afforded compound 2-15 as an off-whitesolid (33 mg, 27%). ¹H NMR (400 MHz, DMSO-d₆): δ 8.54-8.42 (m, 4H), 8.10(br d, J=4.9 Hz, 1H), 7.72-7.63 (m, 1H), 7.42 (d, J=2.9 Hz, 1H), 7.32(br d, J=8.2 Hz, 1H), 7.23 (br dd, J=8.6, 4.4 Hz, 1H), 7.20-7.15 (m,2H), 7.09 (br t, J=7.8 Hz, 1H), 6.73 (d, J=7.5 Hz, 1H), 6.11 (d, J=2.6Hz, 1H), 5.50 (s, 2H), 4.09-4.06 (m, 2H); LCMS Mass: 349.0 (M⁺+1).

Example 48:(2-((1-(Quinolin-2-ylmethyl)-1H-indol-4-yl)oxy)pyridin-4-yl)methanamineHydrochloride (Compound 2-16)

The title compound (2-16) was prepared using the procedure for Example47, using 2-(bromomethyl)quinoline in Step 3. ¹H NMR (500 MHz, DMSO-d₆):δ 8.58 (br s, 2H), 8.46 (br d, J=8.7 Hz, 1H), 8.13 (br d, J=5.5 Hz, 2H),8.02 (br d, J=7.8 Hz, 1H), 7.86 (br t, J=7.5 Hz, 1H), 7.67 (br t, J=7.4Hz, 1H), 7.58 (d, J=2.9 Hz, 1H), 7.40 (br d, J=8.4 Hz, 1H), 7.25-7.19(m, 3H), 7.11 (t, J=8.0 Hz, 1H), 6.77 (d, J=7.5 Hz, 1H), 6.21 (d, J=2.9Hz, 1H), 5.81 (s, 2H), 4.11-4.08 (m, 2H); LCMS Mass: 381.0 (M⁺+1).

Example 49:(2-((1-((2-(Trifluoromethyl)thiazol-5-yl)methyl)-1H-indol-4-yl)oxy)pyridin-4-yl)methanamineHydrochloride (Compound 2-17)

The title compound (2-17) was prepared using the procedure for Example47, using 5-(bromomethyl)-2-(trifluoromethyl)thiazole (for preparationsee U.S. Pat. No. 5,324,837 A1, 1994) in Step 3. LCMS Mass: 405.0(M⁺+1).

Example 50:(2-((1-(6-Methoxypyridin-3-yl)-1H-indol-4-yl)oxy)pyridin-4-yl)methanamineHydrochloride (Compound 2-20)

Step 1:2-((1-(6-Methoxypyridin-3-yl)-1H-indol-4-yl)oxy)isonicotinonitrile (2)

A solution of 2-((1H-indol-4-yl)oxy)isonicotinonitrile 1 (from Example47, Step 1) (100 mg, 0.42 mmol) in toluene (5 mL) was degassed underargon at RT for 30 min. To the mixture were added5-bromo-2-methoxypyridine (88 mg, 0.47 mmol),N,N′-dimethylethylenediamine (15 mg, 0.17 mmol), potassium phosphate(225 mg, 1.1 mmol) and CuI (8 mg, 0.04 mmol). The mixture was sealed andheated at 140° C. for 12 h. The reaction mixture was diluted with EtOAc(30 mL), filtered through a pad of celite, and the residue was washedwith EtOAc (10 mL). The filtrate was partially concentrated underreduced pressure and washed with water (10 mL), dried (Na₂SO₄),filtered, and concentrated under reduced pressure. The residue waspurified (silica gel; eluting 10% EtOAc/hexanes) to afford compound 2 aspale green solid (130 mg, 89%). ¹H NMR (500 MHz, CDCl₃): δ 8.37-8.32 (m,2H), 7.71 (dd, J=8.8, 2.7 Hz, 1H), 7.33-7.26 (m, 2H), 7.25-7.17 (m, 3H),6.98-6.90 (m, 2H), 6.43 (d, J=2.9 Hz, 1H), 4.02 (s, 3H); LCMS Mass:343.0 (M⁺+1).

Step 2:(2-((1-(6-Methoxypyridin-3-yl)-1H-indol-4-yl)oxy)pyridin-4-yl)methanamineHydrochloride (Compound 2-20)

To a stirred solution of compound 2 (130 mg, 0.38 mmol) in THF/MeOH(1:1, 8 mL) at 0° C. were added CoCl₂ (98 mg, 0.76 mmol) and NaBH₄ (144mg, 3.8 mmol) portion wise. The mixture was warmed to RT and stirred for3 h. The reaction mixture was filtered through a pad of celite and theresidue was washed with 10% MeOH in CH₂Cl₂ (20 mL). The filtrate waswashed with brine (10 mL), dried (Na₂SO₄), filtered, and concentratedunder reduced pressure. The residue was purified via trituration withCH₂Cl₂/n-pentane (2×5 mL) to afford the desired amine.

To this amine in CH₂Cl₂ (2 mL) was added 2M HCl in Et₂O (3 mL) at 0° C.and stirred for 30 min. The mixture was concentrated under reducedpressure and the obtained solid triturated with Et₂O/n-pentane (2×5 mL)to afford compound 2-20 as a pale green solid (80 mg, 49%).

¹H NMR (400 MHz, DMSO-d₆): δ 8.68 (br s, 2H), 8.42 (d, J=2.3 Hz, 3H),8.14 (d, J=5.1 Hz, 1H), 7.98 (dd, J=8.8, 2.8 Hz, 1H), 7.55 (d, J=3.2 Hz,1H), 7.31-7.25 (m, 3H), 7.23-7.18 (m, 1H), 7.05 (d, J=8.9 Hz, 1H), 6.88(dd, J=7.6, 0.7 Hz, 1H), 6.32 (dd, J=3.3, 0.7 Hz, 1H), 4.11 (q, J=5.8Hz, 2H), 3.94 (s, 3H); LCMS Mass: 347.1 (M⁺+1).

Example 51:(2-((1-(4-Fluorophenyl)-1H-indol-4-yl)oxy)pyridin-4-yl)methanamineHydrochloride (Compound 2-18)

The title compound (2-18) was prepared using the procedure for Example50, using 1-bromo-4-fluorobenzene in Step 1. LCMS Mass: 334.4 (M⁺+1).

Example 52:(2-((1-(1-Methyl-1H-pyrazol-4-yl)-1H-indol-4-yl)oxy)pyridin-4-yl)methanamineHydrochloride (Compound 2-19)

The title compound (2-19) was prepared using the procedure for Example50, using 4-bromo-1-methyl-1H-pyrazole in Step 1. LCMS Mass: 320.3(M⁺+1).

Example 53:(2-((1-(6-Fluorobenzo[d]thiazol-2-yl)-1H-indol-4-yl)oxy)pyridin-4-yl)methanamineHydrochloride (Compound 2-21)

Step 1:2-((1-(6-Fluorobenzo[d]thiazol-2-yl)-1H-indol-4-yl)oxy)isonicotinonitrile(2)

A mixture of 2-((1H-indol-4-yl)oxy)isonicotinonitrile 1 (from Example47, Step 1) (100 mg, 0.42 mmol), 2-chloro-6-fluorobenzo[d]thiazole (117mg, 0.63 mmol), nBu₄NBr (5 mol %), Cs₂CO₃ (293 mg, 0.9 mmol), and DMF (5mL) was stirred at RT for 16 h. The mixture was partitioned betweenwater and EtOAc. The organic layer was separated, dried (Na₂SO₄),filtered, and concentrated under reduced pressure. The residue waspurified (silica gel; eluting EtOAc/hexanes) to afford compound 2 (125mg, 77%). ¹H NMR (400 MHz, CDCl₃): δ 8.49 (m, 1H), 8.33 (m, 1H), 7.90(m, 1H), 7.61 (m, 1H), 7.53 (m, 1H), 7.46 (m, 1H), 7.21-7.25 (m, 3H),7.09 (m, 1H), 6.56 (m, 1H); LCMS Mass: 387.0 (M⁺+1).

Step 2:(2-((1-(6-Fluorobenzo[d]thiazol-2-yl)-1H-indol-4-yl)oxy)pyridin-4-yl)methanamineHydrochloride (Compound 2-21)

The title compound (2-21) (13 mg, 9%) was prepared from2-((1-(6-fluorobenzo[d]thiazol-2-yl)-1H-indol-4-yl)oxy)isonicotinonitrile2 using the procedure described in Example 50, Step 2. LCMS Mass: 391.0(M⁺+1).

Example 54:(2-((1-(4-Fluorophenethyl)-1H-indol-4-yl)oxy)pyridin-4-yl)methanamineHydrochloride (Compound 2-22)

Step 1: 2-((1-(4-Fluorophenethyl)-1H-indol-4-yl)oxy)isonicotinonitrile(3) and2-((3-bromo-1-(4-fluorophenethyl)-1H-indol-4-yl)oxy)isonicotinonitrile(4)

To a stirred solution of 2-((1H-indol-4-yl)oxy) isonicotinonitrile 1(150 mg, 0.64 mmol) (from Example 47, Step 1) in DMF (5 mL) at 0° C.,were added 1-(2-bromoethyl)-4-fluorobenzene 2 (194 mg, 0.96 mmol),Cs₂CO₃ (416 mg, 1.28 mmol) and nBu₄NBr (10 mg, 0.03 mmol). The mixturewas warmed to RT and stirred for 48 h. The reaction mixture was dilutedwith water (20 mL) and extracted with EtOAc (2×30 mL). The combinedorganic extracts were washed with brine (15 mL), dried (Na₂SO₄),filtered, and concentrated under reduced pressure. The residue waspurified via preparative HPLC to afford compound 3 (70 mg, 30%) andcompound 4 (70 mg, 25%) both as a pale yellow oil.

Analytical data for Compound 3: ¹H NMR (400 MHz, CDCl₃): δ 8.34 (dd,J=5.1, 0.7 Hz, 1H), 7.24-7.22 (m, 2H), 7.18 (dd, J=5.1, 1.3 Hz, 1H),7.09-7.07 (m, 1H), 7.03-6.88 (m, 5H), 6.84 (d, J=3.2 Hz, 1H), 6.16 (d,J=3.1 Hz, 1H), 4.34 (t, J=7.2 Hz, 2H), 3.10 (t, J=7.2 Hz, 2H); LCMSMass: 358.0 (M⁺+1).

Analytical data of Compound 4: ¹H NMR (500 MHz, CDCl₃): δ 8.30 (d, J=4.9Hz, 1H), 7.26-7.21 (m, 2H), 7.19-7.16 (m, 2H), 7.06-6.90 (m, 6H), 4.31(t, J=7.2 Hz, 2H), 3.10 (t, J=7.2 Hz, 2H); LCMS Mass: 438.0 (M⁺+2).

Step 2:(2-((1-(4-Fluorophenethyl)-1H-indol-4-yl)oxy)pyridin-4-yl)methanamineHydrochloride (Compound 2-22)

The title compound (2-22) (100 mg) was prepared from2-((1-(4-fluorophenethyl)-1H-indol-4-yl)oxy)isonicotinonitrile 3 usingthe procedure described in Example 50, Step 2. ¹H NMR (400 MHz,DMSO-d₆): δ 8.45 (br s, 2H), 8.14 (d, J=5.1 Hz, 1H), 7.39 (d, J=8.3 Hz,1H), 7.28-7.18 (m, 4H), 7.17-7.05 (m, 4H), 6.75 (d, J=7.1 Hz, 1H), 6.03(dd, J=3.1, 0.7 Hz, 1H), 4.40 (t, J=7.4 Hz, 2H), 4.09 (q, J=5.7 Hz, 2H),3.07 (t, J=7.4 Hz, 2H); LCMS Mass: 362.6 (M⁺+1).

Example 55:(2-((3-Bromo-1-(4-fluorophenethyl)-1H-indol-4-yl)oxy)pyridin-4-yl)methanamineHydrochloride (Compound 2-23)

The title compound (2-23) was prepared from2-((3-bromo-1-(4-fluorophenethyl)-1H-indol-4-yl)oxy)isonicotinonitrile(compound 4 from Example 54, Step 1) from using the procedure describedin Example 50, Step 2. ¹H NMR (400 MHz, CD₃OD): δ 8.17 (d, J=5.4 Hz,1H), 7.37 (d, J=8.4 Hz, 1H), 7.24 (t, J=8.0 Hz, 1H), 7.17 (d, J=5.3 Hz,1H), 7.13-7.08 (m, 3H), 7.04-7.02 (m, 1H), 6.96 (t, J=8.8 Hz, 2H), 6.84(d, J=7.6 Hz, 1H), 4.42 (t, J=7.0 Hz, 2H), 4.18 (s, 2H), 3.11 (t, J=7.1Hz, 2H); LCMS Mass: 441.4 (M⁺+1).

Example 56:2-(4-((4-(Aminomethyl)pyridin-2-yl)oxy)-1H-indol-1-yl)-N,N-dimethylacetamideHydrochloride (Compound 2-26)

The title compound (2-26) was prepared using the procedure for Example47, using 2-bromo-N,N-dimethylacetamide in Step 3. LCMS Mass: 325.1(M⁺+1).

Example 57:2-(4-((4-(Aminomethyl)pyridin-2-yl)oxy)-1H-indol-1-yl)-1-(piperidin-1-yl)ethanoneHydrochloride (Compound 2-27)

The title compound (2-27) was prepared using the procedure for Example47, using 1-(bromoacetyl)piperidine in Step 3. LCMS Mass: 365.0 (M⁺+1).

Examples 58 and 59: (R) or(S)-2-(4-((4-(Aminomethyl)pyridin-2-yl)oxy)-1H-indol-1-yl)-1-(3-hydroxy-3-(trifluoromethyl)piperidin-1-yl)ethan-1-oneHydrochloride (Enantiomer 1) (Compound 2-28), and (R) or(S)-2-(4-((4-(aminomethyl)pyridin-2-yl)oxy)-1H-indol-1-yl)-1-(3-hydroxy-3-(trifluoromethyl)piperidin-1-yl)ethan-1-oneHydrochloride (Enantiomer 2) (Compound 2-29)

Step 1: tert-Butyl 2-(4-((4-cyanopyridin-2-yl)oxy)-1H-indol-1-yl)acetate(2)

To a stirred solution of 2-((1H-indol-4-yl) oxy)isonicotinonitrile 1(100 mg, 0.42 mmol) (from Example 47, Step 1) in DMF (2.5 mL) at 0° C.,were added tert-butyl 2-bromoacetate (0.09 mL, 0.64 mmol), Cs₂CO₃ (276mg, 0.85 mmol) and nBu₄NBr (7 mg, 0.02 mmol). The mixture was warmed toRT and stirred for 12 h. The reaction mixture was quenched with water(20 mL) and extracted with EtOAc (2×30 mL). The combined organicextracts were washed with brine (15 mL), dried (Na₂SO₄), filtered, andconcentrated under reduced. The residue was purified (silica gel;eluting 15% EtOAc/hexanes) to afford compound 2 as a colorless stickysolid (140 mg, 95%). ¹H NMR (500 MHz, CDCl₃): δ 8.34 (d, J=5.2 Hz, 1H),7.26-7.22 (m, 1H), 7.20-7.16 (m, 2H), 7.11-7.04 (m, 2H), 6.92 (d, J=7.5Hz, 1H), 6.29 (d, J=3.2 Hz, 1H), 4.76 (s, 2H), 1.46 (s, 9H); LCMS Mass:350.0 (M⁺+1).

Step 2: 2-(4-((4-Cyanopyridin-2-yl)oxy)-1H-indol-1-yl)acetic Acid (3)

To a stirred solution of compound 2 (140 mg, 0.4 mmol) in CH₂Cl₂ (4 mL)at 0° C., was added TFA (0.8 mL). The mixture was warmed to RT andstirred for 12 h. The reaction mixture was concentrated under reducedpressure. The residue was diluted with water (20 mL) and extracted withEtOAc (2×30 mL). The combined organic extracts were washed with brine(15 mL), dried (Na₂SO₄), filtered, and concentrated under reducedpressure. The crude was purified via trituration with Et₂O/n-pentane(2×5 mL) to afford compound 3 as an off-white solid (120 mg, 99%). ¹HNMR (400 MHz, DMSO-d₆): δ 12.98 (br s, 1H), 8.31 (dd, J=5.1, 0.7 Hz,1H), 7.61 (t, J=0.9 Hz, 1H), 7.52 (dd, J=5.1, 1.3 Hz, 1H), 7.31-7.26 (m,2H), 7.13 (t, J=7.9 Hz, 1H), 6.82 (d, J=7.5 Hz, 1H), 6.09 (dd, J=3.2,0.7 Hz, 1H), 5.02 (s, 2H); LCMS Mass: 293.9 (M⁺+1).

Step 3:Racemic-2-((1-(2-(3-hydroxy-3-(trifluoromethyl)piperidin-1-yl)-2-oxoethyl)-1H-indol-4-yl)oxy)isonicotinonitrile(4)

To a stirred solution of compound 3 (120 mg, 0.41 mmol) in DMF (10 mL)at 0° C., were added HATU (310 mg, 0.82 mmol) and DIEA (0.14 mL, 0.82mmol). The mixture was warmed to RT and stirred for 20 min. A solutionof racemic-3-(trifluoromethyl)piperidin-3-ol (83 mg, 0.49 mmol) in DMF(2 mL) was added, and the mixture stirred at RT for 16 h. AdditionalDIEA (0.28 mL, 1.63 mmol) was added and stirring continued for 24 h. Thereaction mixture was quenched with water (25 mL) and extracted withEtOAc (2×30 mL). The combined organic extracts were washed with brine(15 mL), dried (Na₂SO₄), filtered, and concentrated under reducedpressure. The residue was purified (silica gel; eluting 15-30%EtOAc/hexanes) to afford compound 4 as a brown solid (80 mg, 44%). LCMSMass: 445.0 (M⁺+1).

Step 4:Racemic-2-(4-((4-(aminomethyl)pyridin-2-yl)oxy)-1H-indol-1-yl)-1-(3-hydroxy-3-(trifluoromethyl)piperidin-1-yl)ethan-1-one(5)

To a stirred solution of compound 4 (80 mg, 0.18 mmol) in THF/MeOH (1:1,6 mL) at 0° C. were added CoCl₂ (46 mg, 0.36 mmol) and NaBH₄ (68 mg, 1.8mmol) portion wise. The mixture was warmed to RT and stirred for 4 h.The reaction mixture was filtered through a pad of celite and theresidue was washed with 10% MeOH/CH₂Cl₂ (30 mL). The filtrate was washedwith brine (10 mL), dried (Na₂SO₄), filtered, and concentrated underreduced pressure. The crude was purified via trituration with n-pentaneto afford compound 5 (35 mg). LCMS Mass: 449.0 (M⁺+1).

Step 5: (R) or(S)-2-(4-((4-(Aminomethyl)pyridin-2-yl)oxy)-1H-indol-1-yl)-1-(3-hydroxy-3-(trifluoromethyl)piperidin-1-yl)ethan-1-oneHydrochloride (Enantiomer 1) (Compound 2-28), and (R) or(S)-2-(4-((4-(aminomethyl)pyridin-2-yl)oxy)-1H-indol-1-yl)-1-(3-hydroxy-3-(trifluoromethyl)piperidin-1-yl)ethan-1-oneHydrochloride (Enantiomer 2) (Compound 2-29)

Racemic-2-(4-((4-(aminomethyl)pyridin-2-yl)oxy)-1H-indol-1-yl)-1-(3-hydroxy-3-(trifluoromethyl)piperidin-1-yl)ethan-1-one(5) was separated via chiral HPLC (Chiralpak-IB, 250×20 mm, 5 μm);mobile phase (A) 0.1% DEA in n-Hexane (B) EtOH (A:B, 65:35); flow Rate:18.0 mL/min) to afford to afford the individual free amine enantiomers.

The first eluting enantiomer (8 mg) was dissolved in THF (2 mL) and tothis was added 2M HCl in Et₂O (3 mL) at 0° C., and the mixture stirredfor 20 min. The obtained solid was collected via filtration and driedunder vacuum to afford compound 2-28 (enantiomer-1) as a white solid(7.5 mg, 87%). ¹H NMR (400 MHz, DMSO-d₆): δ 8.35 (br s, 3H), 8.15 (d,J=5.1 Hz, 1H), 7.22-7.15 (m, 3H), 7.11 (t, J=7.7 Hz, 1H), 6.76 (d, J=7.5Hz, 1H), 6.45 (br s, 1H), 6.08 (d, J=3.0 Hz, 1H), 5.22 (s, 2H),4.29-4.24 (m, 1H), 4.16-4.08 (m, 2H), 3.94-3.88 (m, 1H), 3.44-3.38 (m,1H), 3.25-3.23 (m, 1H), 3.05 (br d, J=13.4 Hz, 1H), 1.88-1.83 (m, 2H),1.70-1.65 (m, 1H), 1.58-1.55 (m, 1H); LCMS Mass: 449.5 (M⁺+1); ChiralHPLC: R_(t)=13.56 min (98.69%); (Chiralpak-IB, 250×4.6 mm, 5 μm); mobilephase (A) 0.1% DEA in n-Hexane (B) CH₂Cl₂: CH₃OH (50:50) (A:B, 70:30);flow Rate: 1.0 mL/min).

The second eluting enantiomer (10 mg) was treated as described above, toafford compound 2-29 (enantiomer-2) as a white solid (8.9 mg, 82%). ¹HNMR (400 MHz, DMSO-d₆): δ 8.47 (br s, 3H), 8.14 (d, J=5.1 Hz, 1H),7.23-7.15 (m, 3H), 7.11 (t, J=7.6 Hz, 1H), 6.76 (d, J=7.4 Hz, 1H), 6.46(br s, 1H), 6.08 (d, J=3.1 Hz, 1H), 5.22 (s, 2H), 4.30-4.24 (m, 1H),4.15-4.07 (m, 2H), 3.94-3.89 (m, 1H), 3.41 (br d, J=14.0 Hz, 1H),3.28-3.19 (m, 1H), 3.05 (br d, J=13.3 Hz, 1H), 1.92-1.78 (m, 2H),1.70-1.65 (m, 1H), 1.58-1.53 (m, 1H); LCMS Mass: 449.5 (M⁺+1); ChiralHPLC: R_(t)=14.74 min (99.58%); (Chiralpak-IB, 250×4.6 mm, 5 μm); mobilephase (A) 0.1% DEA in n-Hexane (B) CH₂Cl₂: CH₃OH (50:50) (A:B, 70:30);flow Rate: 1.0 mL/min).

Example 60:2-(4-((4-(Aminomethyl)pyridin-2-yl)oxy)-1H-indol-1-yl)-N-methyl-N-phenylacetamideHydrochloride (Compound 2-30)

The title compound (2-30) was prepared using the procedure for Example47, using 2-bromo-N-methyl-N-phenylacetamide in Step 3. LCMS Mass: 387.5(M⁺+1).

Example 61:2-(4-((4-(Aminomethyl)pyridin-2-yl)oxy)-1H-indol-1-yl)-1-(3,4-dihydroquinolin-1(2H)-yl)ethanoneHydrochloride (Compound 2-31)

The title compound (2-31) was prepared using the procedure for Example47, using 1-(bromoacetyl)-1,2,3,4-tetrahydroquinoline (prepared asdescribed in WO2003/087057 A1) in Step 3. LCMS Mass: 413.2 (M⁺+1).

Example 62:(4-((4-(Aminomethyl)pyridin-2-yl)oxy)-1H-indol-1-yl)(phenyl)methanoneHydrochloride (Compound 2-24)

Step 1: 2-((1-Benzoyl-1H-indol-4-yl)oxy)isonicotinonitrile (2)

To a stirred solution of 2-((1H-indol-4-yl)oxy)isonicotinonitrile 1 (100mg, 0.42 mmol) (from Example 47, Step 1) in DMF (5 mL) at 0° C., wasadded NaH (26 mg of a 60% in mineral oil, 0.64 mmol). The mixture waswarmed to RT and stirred for 3 h. The mixture was cooled to 0° C., thenbenzoyl chloride (0.05 mL, 0.47 mmol) was added. The mixture was warmedto RT and stirred for 12 h. The reaction mixture was quenched with icecold water (20 mL) and extracted with EtOAc (2×30 mL). The combinedorganic extracts were washed with brine (15 mL), dried (Na₂SO₄),filtered, and concentrated under reduced pressure. The residue waspurified (silica gel; eluting 10% EtOAc/hexanes) to afford compound 2 asa pale yellow solid (85 mg, 59%). ¹H NMR (500 MHz, DMSO-d₆): δ 8.31 (d,J=5.2 Hz, 1H), 8.17 (d, J=8.4 Hz, 1H), 7.78-7.72 (m, 3H), 7.71-7.66 (m,1H), 7.62-7.55 (m, 3H), 7.42 (t, J=8.1 Hz, 1H), 7.34 (d, J=3.8 Hz, 1H),7.14 (d, J=7.8 Hz, 1H), 6.44 (d, J=3.5 Hz, 1H); LCMS Mass: 340.0 (M⁺+1).

Step 2:(4-((4-(Aminomethyl)pyridin-2-yl)oxy)-1H-indol-1-yl)(phenyl)methanoneHydrochloride (Compound 2-24)

The title compound (2-24) (32 mg, 28%) was prepared from2-((1-benzoyl-1H-indol-4-yl)oxy)isonicotinonitrile (2) using theprocedure described in Example 50, Step 2. ¹H NMR (400 MHz, CD₃OD): δ8.26 (br d, J=8.3 Hz, 2H), 7.78-7.74 (m, 2H), 7.68 (t, J=7.4 Hz, 1H),7.59 (t, J=7.2 Hz, 2H), 7.43 (t, J=8.1 Hz, 1H), 7.36 (d, J=3.7 Hz, 1H),7.26-7.24 (m, 1H), 7.16-7.09 (m, 2H), 6.46 (br d, J=3.3 Hz, 1H), 4.21(s, 2H); LCMS Mass: 344.4 (M⁺+1).

Example 63:4-((4-(Aminomethyl)pyridin-2-yl)oxy)-N-phenyl-1H-indole-1-carboxamideHydrochloride (Compound 2-25)

The title compound (2-25) was prepared using the procedure for Example62, using phenyl isocyanate in Step 1. ¹H NMR (500 MHz, DMSO-d₆): δ10.18 (s, 1H), 8.50 (s, 3H), 8.14 (d, J=5.5 Hz, 1H), 8.09 (d, J=8.4 Hz,1H), 8.02 (d, J=3.8 Hz, 1H), 7.65 (d, J=7.8 Hz, 2H), 7.38 (t, J=8.0 Hz,2H), 7.32 (t, J=8.1 Hz, 1H), 7.24-7.20 (m, 2H), 7.14 (t, J=7.4 Hz, 1H),6.96 (d, J=7.8 Hz, 1H), 6.38 (d, J=3.5 Hz, 1H), 4.14-4.10 (m, 2H); LCMSMass: 359.3 (M⁺+1).

Example 64:(2-((1-(2,4-Difluorobenzyl)-2-methyl-1H-indol-4-yl)oxy)pyridin-4-yl)methanamineTrifluoroacetate (Compound 2-11)

The title compound (2-11) was prepared using the procedure for Example46, using 2-methyl-1H-indol-4-ol in Step 1, and 2,4-difluorobenzylbromide in Step 2. The free base form of the title compound, waspurified via preparative HPLC (Waters XTerra® Prep MS C-18 OBD 5 μM50×100 mm column; eluting with 10-90% ACN/H₂O containing 0.1% TFA, over20 min) to yield the TFA salt. LCMS Mass: 380.0 (M⁺+1).

Example 65:(2-((1-(2,4-Difluorobenzyl)-3-methyl-1H-indol-4-yl)oxy)pyridin-4-yl)methanamineTrifluoroacetate (Compound 2-12)

The title compound (2-12) was prepared using the procedure for Example46, using 3-methyl-1H-indol-4-ol in Step 1, and 2,4-difluorobenzylbromide in Step 2. The free base form of the title compound, waspurified via preparative HPLC (Waters XTerra® Prep MS C-18 OBD 5 μM50×100 mm column; eluting with 10-90% ACN/H₂O containing 0.1% TFA, over20 min) to yield the TFA salt. LCMS Mass: 380.0 (M⁺+1).

Example 66:(2-((1-((6-Methoxypyridin-3-yl)methyl)-2-methyl-1H-indol-4-yl)oxy)pyridin-4-yl)methanamineTrifluoroacetate (Compound 2-13)

The title compound (2-13) was prepared using the procedure for Example46, using 2-methyl-1H-indol-4-ol in Step 1, and5-(chloromethyl)-2-methoxypyridine in Step 2. The free base form of thetitle compound, was purified via preparative HPLC (Waters XTerra® PrepMS C-18 OBD 5 μM 50×100 mm column; eluting with 10-90% ACN/H₂Ocontaining 0.1% TFA, over 20 min) to yield the TFA salt. LCMS Mass:375.0 (M⁺+1).

Example 67:(2-((1-((6-Methoxypyridin-3-yl)methyl)-3-methyl-1H-indol-4-yl)oxy)pyridin-4-yl)methanamineTrifluoroacetate (Compound 2-14)

The title compound (2-14) was prepared using the procedure for Example46, using 3-methyl-1H-indol-4-ol in Step 1, and5-(chloromethyl)-2-methoxypyridine in Step 2. The free base form of thetitle compound, was purified via preparative HPLC (Waters XTerra® PrepMS C-18 OBD 5 μM 50×100 mm column; eluting with 10-90% ACN/H₂Ocontaining 0.1% TFA, over 20 min) to yield the TFA salt. LCMS Mass:375.0 (M⁺+1).

Example 68:(2-((1-(2,4-Difluorobenzyl)-3-methyl-1H-indazol-4-yl)oxy)pyridin-4-yl)methanamineTrifluoroacetate (Compound 2-35)

The title compound (2-35) was prepared using the procedure for Example46, using 3-methyl-1H-indazol-4-ol in Step 1, and 2,4-difluorobenzylbromide in Step 2. The free base form of the title compound, waspurified via preparative HPLC (Waters XTerra® Prep MS C-18 OBD 5 μM50×100 mm column; eluting with 10-90% ACN/H₂O containing 0.1% TFA, over20 min) to yield the TFA salt. LCMS Mass: 381.0 (M⁺+1).

Example 69:5-((4-(Aminomethyl)pyridin-2-yl)oxy)-1-(2,4-difluorobenzyl)-3,4-dihydroquinolin-2(1H)-oneHydrochloride (Compound 2-36)

The title compound (2-36) was prepared using the procedure for Example46, using 5-hydroxy-3,4-dihydroquinolin-2(1H)-one in Step 1, and2,4-difluorobenzyl bromide in Step 2. LCMS Mass: 396.0 (M⁺+1).

Example 70:5-((4-(Aminomethyl)pyridin-2-yl)oxy)-1-((6-methoxypyridin-3-yl)methyl)-3,4-dihydroquinolin-2(1H)-oneAcetate (Compound 2-37)

The title compound (2-37) was prepared using the procedure for Example46, using 5-hydroxy-3,4-dihydroquinolin-2(1H)-one in Step 1, and5-(chloromethyl)-2-methoxypyridine in Step 2. In step 5, directpurification via trituration with EtOAc afforded the acetate salt. LCMSMass: 391.0 (M⁺+1).

Example 71:(2-((1-((6-Methoxypyridin-3-yl)methyl)-1H-indol-5-yl)oxy)pyridin-4-yl)methanamineTrifluoroacetate (Compound 2-34)

The title compound (2-34) was prepared using the procedure for Example46, using 5-hydroxy-1H-indole in Step 1, and5-(chloromethyl)-2-methoxypyridine in Step 2. The free base form of thetitle compound, was purified via preparative HPLC (Waters XTerra® PrepMS C-18 OBD 5 μM 50×100 mm column; eluting with 10-90% ACN/H₂Ocontaining 0.1% TFA, over 20 min) to yield the TFA salt. LCMS Mass:361.0 (M⁺+1).

Example 72:(2-((1-(6-Fluorobenzo[d]thiazol-2-yl)indolin-4-yl)oxy)pyridin-4-yl)methanamineHydrochloride (Compound 2-33)

The title compound (2-33) (31 mg, 25%) was prepared from2-((1-(6-fluorobenzo[d]thiazol-2-yl)-1H-indol-4-yl)oxy)isonicotinonitrile(from Example 53, Step 1) using the procedure described in Example 50,Step 2. ¹H NMR (400 MHz, DMSO-d₆): δ 8.45 (br s, 3H), 8.20 (m, 1H), 8.10(m, 1H), 7.88 (m, 1H), 7.70 (m, 1H), 7.36 (m, 1H), 7.18-7.20 (m, 3H),6.78 (m, 1H), 4.10-4.21 (m, 4H), 3.01-3.10 (m, 2H); LCMS Mass: 393.4(M⁺+1).

Example 73: (2-((1H-Indol-4-yl)oxy)pyridin-4-yl)methanamineTrifluoroacetate (Compound 2-32)

The title compound (2-32) was prepared from2-((1H-indol-4-yl)oxy)isonicotinonitrile (from Example 47, Step 1) usingthe procedure described for the synthesis of A-3 (see synthesis ofInt-A, Step 2). The free base form of the title compound, was purifiedvia preparative HPLC (Waters XTerra® Prep MS C-18 OBD 5 μM 50×100 mmcolumn; eluting with 10-90% ACN/H₂O containing 0.1% TFA, over 20 min) toyield the TFA salt. LCMS Mass: 240.4 (M⁺+1).

Example 74:(S)-(3-((4-(Aminomethyl)pyridin-2-yl)oxy)piperidin-1-yl)(phenyl)methanoneTrifluoroacetate (Compound 2-38)

Step 1: (S)-tert-Butyl3-((4-cyanopyridin-2-yl)oxy)piperidine-1-carboxylate (2)

To a stirred solution of (S)-1-boc-3-hydroxypiperidine (1 g, 4.97 mmol)in THF (25 mL) at 0° C., was added NaH (203 mg of a 60% dispersion inmineral oil, 5.07 mmol). The mixture was stirred at 0° C. for 10 min.2-Chloro-4-pyridinecarbonitrile (1) (688 mg, 4.97 mmol) was added andthe mixture allowed to warm to RT and stirred for 1.5 h. The mixture wasthen heated at 70° C. for 19 h. The mixture was cooled to RT and dilutedwith water (25 mL), brine (25 mL) and aq. sat. NH₄Cl solution (25 mL).The mixture was extracted with EtOAc (3×20 mL). The combined organiclayers were dried (MgSO₄), filtered, and concentrated under reducedpressure. The residue was purified (silica gel; eluting 0-40%EtOAc/hexanes) to afford compound 2 as a colorless oil (875 mg, 58%). ¹HNMR (300 MHz, DMSO-d₆): δ 8.39 (m, 1H), 7.40 (m, 1H), 7.34 (br s, 1H),4.99 (m, 1H), 3.75 (br m, 1H), 3.20 (br m, 1H), 1.60-2.00 (br m, 2H),1.20-1.50 (br m, 4H), 1.10 (br s, 9H); LCMS Mass: 204.0 (M⁺+2−Boc).

Step 2: (S)-2-(Piperidin-3-yloxy)isonicotinonitrile Hydrochloride (3)

The title compound (3) (688 mg, 100%) was prepared from compound 2 usingthe procedure described in Example 1, Step 2. ¹H NMR (300 MHz, DMSO-d₆):δ 9.50 (br s, 1H), 9.06 (br s, 1H), 8.39 (m, 1H), 7.45 (m, 1H), 7.35 (m,1H), 5.30 (m, 1H), 3.35 (m, 1H), 3.15 (m, 1H), 2.95-3.10 (m, 2H),1.65-2.00 (m, 4H); LCMS Mass: 204.0 (M⁺+1).

Step 3: (S)-2-((1-Benzoylpiperidin-3-yl)oxy)isonicotinonitrile (4)

To a stirred solution of benzoic acid (51 mg, 0.417 mmol) in DMF (3 mL),was added HATU (317 mg, 0.834 mmol) and the mixture was stirred at RTfor 20 min. To the mixture were added compound 3 (100 mg, 0.417 mmol)and DIEA (161 mg, 1.25 mmol), and the mixture stirred at RT for 16 h.The mixture was diluted with water (20 mL), brine (20 mL), and aq. 2MHCl (5 mL). The mixture was extracted with EtOAc (4×10 mL) and thecombined organic layers were dried (MgSO₄), filtered, and thenconcentrated under reduced pressure. The crude residue was purified(silica gel; eluting with 0-60% EtOAc in hexanes), to afford compound 4as an oil (64 mg, 50%). LCMS Mass: 308.0 (M⁺+1).

Step 4:(S)-(3-((4-(Aminomethyl)pyridin-2-yl)oxy)piperidin-1-yl)(phenyl)methanoneTrifluoroacetate (Compound 2-38)

The title compound (2-38) was prepared from compound 4 using theprocedure described for the synthesis of A-3 (see synthesis of Int-A,Step 2). The free base form of the title compound, was purified viapreparative HPLC (Waters XTerra® Prep MS C-18 OBD 5 μM 50×100 mm column;eluting with 10-90% ACN/H₂O containing 0.1% TFA, over 20 min) to yieldthe TFA salt. LCMS Mass: 312.0 (M⁺+1).

Example 75:(S)-3-((4-(Aminomethyl)pyridin-2-yl)oxy)-N-phenylpiperidine-1-carboxamideTrifluoroacetate (Compound 2-39)

Step 1:(S)-3-((4-Cyanopyridin-2-yl)oxy)-N-phenylpiperidine-1-carboxamide (2)

A mixture of phenyl isocyanate (149 mg, 1.25 mmol), DIEA (324 mg, 2.5mmol), and THF (5 mL) was stirred at RT for 10 min.(S)-2-(piperidin-3-yloxy)isonicotinonitrile.HCl (from Example 74, Step2) (200 mg, 0.834 mmol) was added and the mixture stirred at RT for 15min. The mixture was concentrated under reduced pressure and the residuepurified (silica gel; eluting with 0-50% EtOAc in hexanes), to affordcompound 2 as a colorless oil (180 mg, 67%). ¹H NMR (300 MHz, DMSO-d₆):δ 8.35-8.45 (m, 2H), 7.10-7.50 (m, 6H), 6.90 (m, 1H), 5.06 (m, 1H), 3.80(m, 1H), 3.40-3.60 (m, 3H), 1.45-2.10 (m, 4H); LCMS Mass: 323.0 (M⁺+1).

Step 2:(S)-3-((4-(Aminomethyl)pyridin-2-yl)oxy)-N-phenylpiperidine-1-carboxamideTrifluoroacetate (Compound 2-39)

The title compound (2-39) was prepared from compound 2 using theprocedure described for the synthesis of A-3 (see synthesis of Int-A,Step 2). The free base form of the title compound, was purified viapreparative HPLC (Waters XTerra® Prep MS C-18 OBD 5 μM 50×100 mm column;eluting with 10-90% ACN/H₂O containing 0.1% TFA, over 20 min) to yieldthe TFA salt. ¹H NMR (300 MHz, DMSO-d₆): δ 8.47 (m, 1H), 8.22 (br s,3H), 8.17 (m, 1H), 7.36-7.42 (m, 2H), 7.14-7.22 (m, 2H), 7.00 (m, 1H),6.82-6.92 (m, 2H), 5.06 (m, 1H), 3.95-4.05 (m, 2H), 3.79 (m, 1H),3.35-3.55 (m, 3H), 2.00 (m, 1H), 1.50-1.80 (m, 3H); LCMS Mass: 327.0(M⁺+1).

Example 76: 3-((4-(Aminomethyl)pyridin-2-yl)oxy)benzoic AcidHydrochloride (Compound 2-5)

The title compound (2-5) was prepared directly from Int-B using theprocedure described in Example 1, Step 2. LCMS Mass: 229.0 (M⁺+1).

Example 77: 4-(4-(Aminomethyl)pyridin-2-yl)benzoic acid trifluoroacetate(Compound 2-6)

The title compound (2-6) was prepared directly from Int-A using theprocedure described in Example 1, Step 2. The hydrochloride salt form ofthe title compound, was purified via preparative HPLC (Waters XTerra®Prep MS C-18 OBD 5 μM 50×100 mm column; eluting with 10-90% ACN/H₂Ocontaining 0.1% TFA, over 20 min) to yield the TFA salt. LCMS Mass:229.0 (M⁺+1).

Example 78:Racemic-trans-(1-(4-(aminomethyl)pyridin-2-yl)-4-fluoropyrrolidin-3-ol(Compound 2-1)

Step 1:Racemic-trans-2-(3-fluoro-4-hydroxypyrrolidin-1-yl)isonicotinonitrile(2)

A stirred mixture of 2-chloro-4-pyridinecarbonitrile (1) (250 mg, 1.804mmol), DIEA (466 mg, 3.61 mmol),racemic-trans-4-fluoro-3-hydroxypyrrolidine hydrochloride (306 mg, 2.16mmol), and DMA (4 mL), was heated at 120° C. for 4 h. The mixture wascooled to RT then partitioned between water (50 mL) and EtOAc (30 mL).The organic layer was separated, dried (MgSO₄), filtered, andconcentrated under reduced pressure. The residue was purified (silicagel; eluting with 0-100% EtOAc in hexanes), to afford compound 2-1 as asolid. ¹H NMR (300 MHz, DMSO-d₆): δ 8.25 (m, 1H), 6.95 (m, 1H), 6.90 (m,1H), 5.58 (m, 1H), 5.08 (m, 1H), 4.34 (m, 1H), 3.73 (m, 1H), 3.40-3.70(m, 3H); LCMS Mass: 208.0 (M⁺+1).

Step 2:Racemic-trans-(1-(4-(aminomethyl)pyridin-2-yl)-4-fluoropyrrolidin-3-ol(Compound 2-1)

A mixture of nitrile (2), 10 wt % Pd/C (5 mol %) and MeOH (20 mL), wasstirred under H₂ gas (balloon) at RT for 16 h. The mixture was filteredthrough celite and the celite washed with additional MeOH (20 mL). Thecombined filtrates were concentrated under reduced pressure. The residuewas purified (silica gel; eluting first with 0-100% EtOAc in hexanes,then 0-20% MeOH in DCM) to afford compound 2-1 as a solid (61 mg). ¹HNMR (300 MHz, DMSO-d₆): δ 7.94 (m, 1H), 6.54 (m, 1H), 6.45 (m, 1H), 5.03(m, 1H), 4.32 (m, 1H), 3.38-3.70 (m, 7H); LCMS Mass: 212.0 (M⁺+1).

Example 79:Racemic-1-(4-(Aminomethyl)pyridin-2-yl)-3-(trifluoromethyl)pyrrolidin-3-ol(Compound 2-2)

The title compound (2-2) was prepared using the procedure described inExample 78, using racemic-3-(trifluoromethyl)pyrrolidin-3-ol in Step 1.LCMS Mass: 262.0 (M⁺+1).

Example 80: [2,3′-Bipyridin]-4-ylmethanamine (Compound 2-3)

Step 1: [2,3′-bipyridine]-4-carbonitrile (2)

A stirred solution of 2-chloro-4-pyridinecarbonitrile (1) (250 mg, 1.804mmol), pyridine-3-boronic acid (332 mg, 2.71 mmol), aq. 2M Na₂CO₃ (1 mL,2.0 mmol) and MeCN (3 mL), was purged with a stream of N₂ for 10 min atRT. To the mixture was added Pd(dppf)Cl₂. DCM (66 mg, 0.09 mmol). Themixture was sealed and heated at 100° C. for 1 h. After cooling to RT,the mixture was partitioned between water (25 mL) and EtOAc (25 ml). Theorganic layer was separated, dried (MgSO₄), filtered, and thenconcentrated under reduced pressure. The residue was purified (silicagel; eluting with 0-100% EtOAc in hexanes) to afford compound 2 as awhite solid (243 mg, 75%). ¹H NMR (300 MHz, DMSO-d₆): δ 9.31 (m, 1H),8.94 (m, 1H), 8.68 (m, 1H), 8.58 (m, 1H), 8.48 (m, 1H), 7.88 (m, 1H),7.55 (m, 1H); LCMS Mass: 182.0 (M⁺+1).

Step 2: [2,3′-Bipyridin]-4-ylmethanamine (Compound 2-3)

The title compound (2-3) was prepared from compound 2 using theprocedure described in Example 78, Step 2. ¹H NMR (300 MHz, DMSO-d₆): δ9.25 (m, 1H), 8.56-8.70 (m, 2H), 8.41 (m, 1H), 8.01 (m, 1H), 7.51 (m,1H), 7.36 (m, 1H), 3.78 (s, 2H), 2.05 (br s, 2H); LCMS Mass: 186.0(M⁺+1).

Example 81: (2-(4-Fluorophenyl)pyridin-4-yl)methanamine (Compound 2-4)

The title compound (2-4) was prepared using the procedure described inExample 80, using 4-fluorophenylboronic acid in Step 1. LCMS Mass: 203.0(M⁺+1).

Example 82: 4-((4-(Aminomethyl)pyridin-2-yl)oxy)benzoic AcidHydrochloride (Compound 2-9)

The title compound (2-9) was prepared directly from Int-C using theprocedure described in Example 1, Step 2. LCMS Mass: 245.0 (M⁺+1).

Example 83: (2-Phenoxypyridin-4-yl)methanamine Hydrochloride (Compound2-7)

Step 1: 2-phenoxyisonicotinonitrile (2)

A mixture of phenol (679 mg, 7.22 mmol), Cs₂CO₃ (3.53 g, 10.83 mmol),and DMA (10 mL) was stirred at RT for 30 min.2-Chloro-4-pyridinecarbonitrile (1) (1.0 g, 7.22 mmol) was added and themixture heated at 80° C. for 20 h. The mixture was cooled to RT anddiluted with water (100 mL), brine (15 mL), and aq. 2M HCl (15 mL). Themixture was extracted with EtOAc (2×50 mL) and the combined organiclayers were dried (MgSO₄), filtered, and then concentrated under reducedpressure to afford compound 2 as a white solid (1.34 g, 95%) which didnot require further purification. ¹H NMR (300 MHz, DMSO-d₆): δ 8.35 (m,1H), 7.62 (m, 1H), 7.55 (m, 1H), 7.40-7.46 (m, 2H), 7.24 (m, 1H),7.14-7.17 (m, 2H); LCMS Mass: 197.0 (M⁺+1).

Step 2: (2-Phenoxypyridin-4-yl)methanamine (3)

The title compound (3) (231 mg, 91%) was prepared from compound 2 (250mg, 1.27 mmol) using the procedure described for the synthesis of A-3(see synthesis of Int-A, Step 2). ¹H NMR (300 MHz, DMSO-d₆): δ 8.02 (m,1H), 7.34-7.44 (m, 2H), 6.99-7.21 (m, 5H), 3.71-3.73 (m, 2H).

Step 3: (2-Phenoxypyridin-4-yl)methanamine Hydrochloride (Compound 2-7)

To a stirred solution of (2-phenoxypyridin-4-yl)methanamine (3) (213 mg,1.15 mmol) in DCM (2 mL) at RT, was added 2M HCl in Et₂O (2 mL, 4.0mmol) and the mixture stirred for 15 min. The mixture was concentratedunder reduced pressure, to afford compound 2-7 as a white solid (272 mg,100%). LCMS Mass: 201.0 (M⁺+1).

Example 84: (2-(3-Phenoxyphenoxy)pyridin-4-yl)methanamine (Compound 2-8)

The title compound (2-8) was prepared using the procedure for Example83, Steps 1 and 2, using 3-phenoxyphenol in Step 1. LCMS Mass: 293.0(M⁺+1).

Example 85:Racemic-(4-(aminomethyl)pyridin-2-yl)(3-hydroxy-3-(trifluoromethyl)pyrrolidin-1-yl)methanonehydrochloride (Compound 2-40)

Step 1: Racemic tert-butyl((2-(3-hydroxy-3-(trifluoromethyl)pyrrolidine-1-carbonyl)pyridin-4-yl)methyl)carbamate (2)

The title compound (2) (30 mg, 26%) was prepared from4-[(tert-butoxycarbonylamino) methyl]pyridine-2-carboxylic acid (1) andracemic-3-(trifluoromethyl)pyrrolidin-3-ol.HCl, using the procedure forExample 1, Step 1. LCMS Mass: 390.0 (M⁺+1).

Step 2:Racemic-(4-(aminomethyl)pyridin-2-yl)(3-hydroxy-3-(trifluoromethyl)pyrrolidin-1-yl)methanoneHydrochloride (Compound 2-40)

The title compound (2-40) was prepared from compound 2 using theprocedure described in Example 1, Step 2. ¹H NMR (300 MHz, DMSO-d₆): δ8.65 (m, 1H), 8.58 (br s, 3H), 7.94 (m, 1H), 7.62 (m, 1H), 4.10-4.20 (m,2H), 3.60-4.00 (m, 4H), 2.00-2.20 (m, 2H); LCMS Mass: 290.0 (M⁺+1).

Example 86: 4-(Aminomethyl)-N-benzylpicolinamide (Compound 2-41)

The title compound (2-41) was prepared using the procedure for Example85, using benzylamine in Step 1. LCMS Mass: 242.0 (M⁺+1).

Example 87: N-(4-(Aminomethyl)pyridin-2-yl)-2-fluoro-4-methylbenzamideTrifluoroacetate (Compound 2-42)

Step 1: N-(4-Cyanopyridin-2-yl)-2-fluoro-4-methylbenzamide (2)

To a stirred solution of 2-fluoro-4-methylbenzoic acid (168 mg, 1.09mmol) in DCM (2 mL), was added HATU (479 mg, 1.26 mmol) and the mixturewas stirred at RT for 10 min. 2-Amino-isonicotinonitrile (1) (100 mg,0.839 mmol) and DIEA (325 mg, 2.51 mmol) were added and the mixturestirred at RT for 20 h. The DCM was evaporated under reduced pressureand the remaining reaction mixture was partitioned between water (20 mL)and EtOAc (20 mL). The organic layer was separated, dried (Na₂SO₄),filtered, and then concentrated under reduced pressure. The cruderesidue was purified (silica gel; eluting with 0-100% EtOAc in hexanes),to afford compound 2 as a white solid (40 mg, 19%). LCMS Mass: 256.0(M⁺+1).

Step 2: N-(4-(Aminomethyl)pyridin-2-yl)-2-fluoro-4-methylbenzamideTrifluoroacetate (Compound 2-42)

A mixture of compound 2 (40 mg, 0.157 mmol), 10 wt % Pd on C (0.0078mmol, 5 mol %) and EtOAc: MeOH (1:1, 15 mL), was stirred under H₂ gas(balloon) at RT for 3 h. The mixture was filtered through celite and thecelite washed with additional MeOH (15 mL). The combined filtrates wereconcentrated under reduced pressure. The residue was purified viapreparative HPLC (Waters XTerra® Prep MS C-18 OBD 5 μM 50×100 mm column;eluting with 10-90% ACN/H₂O containing 0.1% TFA, over 20 min) to affordcompound 2-42 as a solid (10 mg, 25%). ¹H NMR (300 MHz, MeOH-d₄): δ8.40-8.50 (m, 2H), 7.75 (m, 1H), 7.00-7.30 (m, 3H), 4.20 (s, 2H), 2.45(s, 3H); LCMS Mass: 260.0 (M⁺+1).

Example 88:N-(4-(Aminomethyl)pyridin-2-yl)-2-(3,4-dichlorophenyl)acetamideTrifluoroacetate (Compound 2-43)

The title compound (2-43) was prepared using the procedure for Example87, using 3,4-dichlorophenylacetic acid in Step 1. LCMS Mass: 310.0(M⁺+1).

Example 89:4-(Aminomethyl)-N,N-dimethyl-6-(3-phenoxyphenoxy)pyridin-2-amineHydrochloride (Compound 3-1)

Step 1: 2-Chloro-6-(3-phenoxyphenoxy)isonicotinonitrile (2)

A mixture of 2,6-dichloroisonicotinonitrile (1) (500 mg, 2.89 mmol),Cs₂CO₃ (1.41 g, 4.34 mmol), 3-phenoxyphenol (538 mg, 2.89 mmol), and DMA(10 mL), was stirred at RT for 16 h. The reaction mixture was dilutedwith water (100 mL), brine (10 mL), and aq. 2M HCl (3 mL). The mixturewas extracted with EtOAc (4×20 mL) and the combined organic layers weredried (MgSO₄), filtered, and then concentrated under reduced pressure,to afford compound 2 as a amber oil (894 mg, 96%) which did not requirefurther purification. LCMS Mass: 323.0 (M⁺+1).

Step 2: 2-(Dimethylamino)-6-(3-phenoxyphenoxy)isonicotinonitrile (3)

A stirred mixture of compound 2 (108 mg, 0.335 mmol) and 2Mdimethylamine solution in THF (4 mL, 8.0 mmol) was sealed and heated at80° C. for 3.5 h. The mixture was concentrated under reduced pressure toafford compound 3 as a yellow oil (112 mg, 100%) which did not requirefurther purification. ¹H NMR (300 MHz, DMSO-d₆): δ 7.35-7.43 (m, 3H),7.14 (m, 1H), 7.00-7.06 (m, 2H), 6.85-6.95 (m, 2H), 6.70-6.80 (m, 2H),6.45 (m, 1H), 2.88 (s, 6H); LCMS Mass: 332.0 (M⁺+1).

Step 3: 4-(Aminomethyl)-N,N-dimethyl-6-(3-phenoxyphenoxy)pyridin-2-amine(4)

A mixture of compound 3 (108 mg, 0.326 mmol), 10 wt % Pd on C (0.0163mmol, 5 mol %) and EtOAc: MeOH (1:1, 1.0 mL), was stirred under H₂ gas(balloon) at RT for 3 h. The mixture was filtered through celite and thecelite washed with additional MeOH (5 mL). The combined filtrates wereconcentrated under reduced pressure. The residue was purified (silicagel; eluting first with 0-100% EtOAc in hexanes, then 0-10% MeOH inDCM), to afford compound 4 as a white solid (23 mg, 21%). ¹H NMR (300MHz, DMSO-d₆): δ 7.36-7.41 (m, 3H), 7.14 (m, 1H), 7.02-7.05 (m, 2H),6.80-6.89 (m, 2H), 6.72 (m, 1H), 6.44 (m, 1H), 6.20 (m, 1H), 3.86 (s,2H), 2.88 (s, 6H); LCMS Mass: 336.0 (M⁺+1).

Step 4: 4-(Aminomethyl)-N,N-dimethyl-6-(3-phenoxyphenoxy)pyridin-2-amineHydrochloride (Compound 3-1)

To a stirred solution of4-(aminomethyl)-N,N-dimethyl-6-(3-phenoxyphenoxy)pyridin-2-amine (4) (18mg, 0.0537 mmol) in a mixture of THF (2 mL) and DCM (0.5 mL) at RT, wasadded 4M HCl in 1,4-dioxane (0.20 mL, 0.8 mmol). After stirring for 10min, the mixture was concentrated under reduced pressure to affordcompound 3-1 as a yellow solid (4 mg, 20%). ¹H NMR (300 MHz, DMSO-d₆): δ8.50 (br s, 3H), 7.36-7.41 (m, 3H), 7.14 (m, 1H), 7.02-7.05 (m, 2H),6.80-6.89 (m, 2H), 6.70 (m, 1H), 6.49 (m, 1H), 6.23 (m, 1H), 3.86-3.96(m, 2H), 2.88 (s, 6H); LCMS Mass: 336.0 (M⁺+1).

Example 90:4-(Aminomethyl)-N-(2-methoxyethyl)-6-(3-phenoxyphenoxy)pyridin-2-amineTrifluoroacetate (Compound 3-2)

The title compound (3-2) was prepared using the procedure for Example89, Steps 1 through 3, using 2-methoxyethylamine (5 eq.) and Et₃N (5eq.) in Step 2. The free base form of the title compound, was purifiedvia preparative HPLC (Waters XTerra® Prep MS C-18 OBD 5 μM 50×100 mmcolumn; eluting with 10-90% ACN/H₂O containing 0.1% TFA, over 20 min) toyield the TFA salt. LCMS Mass: 366.0 (M⁺+1).

Example 91:(2-(4-Fluorophenyl)-6-(3-phenoxyphenoxy)pyridin-4-yl)methanamineTrifluoroacetate (Compound 3-3)

Step 1: 2-(4-Fluorophenyl)-6-(3-phenoxyphenoxy)isonicotinonitrile (2)

A stirred solution of 2-chloro-6-(3-phenoxyphenoxy)isonicotinonitrile(1) (from Example 89, Step 1) (100 mg, 0.310 mmol),4-fluorophenylboronic acid (65 mg, 0.465 mmol), aq. 2M Na₂CO₃ (0.5 mL,1.0 mmol) and MeCN (1.5 mL), was purged with a stream of nitrogen for 10min at RT. To the mixture was added Pd(dppf)Cl₂. DCM (11 mg, 0.015mmol). The mixture was sealed and heated at 80° C. for 45 min. Aftercooling to RT, the mixture was partitioned between water (25 mL) andEtOAc (25 ml). The organic layer was separated, dried (MgSO₄), filtered,and then concentrated under reduced pressure. The residue was purified(silica gel; eluting with 0-20% EtOAc in hexanes) to afford compound 2as a colorless oil (47 mg, 39%). ¹H NMR (300 MHz, DMSO-d₆): δ 8.21 (m,1H), 7.95-8.00 (m, 2H), 7.56 (m, 1H), 7.47 (m, 1H), 7.28-7.38 (m, 4H),7.00-7.15 (m, 4H), 6.88-6.98 (m, 2H); LCMS Mass: 383.0 (M⁺+1).

Step 2: (2-(4-Fluorophenyl)-6-(3-phenoxyphenoxy)pyridin-4-yl)methanamineTrifluoroacetate (Compound 3-3)

The title compound (3-3) (21 mg, 44%) was prepared from compound 2 usingthe procedure for Example 89, Step 3. The free base form of the titlecompound, was purified via preparative HPLC (Waters XTerra® Prep MS C-18OBD 5 μM 50×100 mm column; eluting with 10-90% ACN/H₂O containing 0.1%TFA, over 20 min) to yield the TFA salt. ¹H NMR (300 MHz, DMSO-d₆): δ8.32 (br s, 3H), 7.86-7.94 (m, 2H), 7.81 (m, 1H), 7.45 (m, 1H),7.28-7.38 (m, 4H), 6.88-7.16 (m, 6H), 6.80 (m, 1H), 4.10-4.20 (m, 2H);LCMS Mass: 387.0 (M⁺+1).

Example 92: 4-(Aminomethyl)-N-(2-methoxyethyl)picolinamide Hydrochloride(Compound 4-13)

The title compound (4-13) was prepared using the procedure for Example85, using 2-methoxyethanamine in Step 1. LCMS Mass: 210.0 (M⁺+1).

Example 93: 4-(Aminomethyl)-N-(2,2,2-trifluoroethyl)picolinamideTrifluoroacetate (Compound 4-14)

The title compound (4-14) was prepared using the procedure for Example87, using 3,3,3-trifluoropropanoic acid in Step 1. LCMS Mass: 234.0(M⁺+1).

Example A-1: Parenteral Pharmaceutical Composition

To prepare a parenteral pharmaceutical composition suitable foradministration by injection (subcutaneous, intravenous), 1-1000 mg of acompound described herein, or a pharmaceutically acceptable salt orsolvate thereof, is dissolved in sterile water and then mixed with 10 mLof 0.9% sterile saline. A suitable buffer is optionally added as well asoptional acid or base to adjust the pH. The mixture is incorporated intoa dosage unit form suitable for administration by injection

Example A-2: Oral Solution

To prepare a pharmaceutical composition for oral delivery, a sufficientamount of a compound described herein, or a pharmaceutically acceptablesalt thereof, is added to water (with optional solubilizer(s), optionalbuffer(s) and taste masking excipients) to provide a 20 mg/mL solution

Example A-3: Oral Tablet

A tablet is prepared by mixing 20-50% by weight of a compound describedherein, or a pharmaceutically acceptable salt thereof, 20-50% by weightof microcrystalline cellulose, 1-10% by weight of low-substitutedhydroxypropyl cellulose, and 1-10% by weight of magnesium stearate orother appropriate excipients. Tablets are prepared by directcompression. The total weight of the compressed tablets is maintained at100-500 mg.

Example A-4: Oral Capsule

To prepare a pharmaceutical composition for oral delivery, 10-500 mg ofa compound described herein, or a pharmaceutically acceptable saltthereof, is mixed with starch or other suitable powder blend. Themixture is incorporated into an oral dosage unit such as a hard gelatincapsule, which is suitable for oral administration.

In another embodiment, 10-500 mg of a compound described herein, or apharmaceutically acceptable salt thereof, is placed into Size 4 capsule,or size 1 capsule (hypromellose or hard gelatin) and the capsule isclosed.

Example A-5: Topical Gel Composition

To prepare a pharmaceutical topical gel composition, a compounddescribed herein, or a pharmaceutically acceptable salt thereof, ismixed with hydroxypropyl celluose, propylene glycol, isopropyl myristateand purified alcohol USP. The resulting gel mixture is then incorporatedinto containers, such as tubes, which are suitable for topicaladministration.

Example B-1: Human LOXL2 Amine Oxidase Activity Assay

LOXL2 amine oxidase activity is evaluated by measuring Amplex Redfluorescence using 10-20× concentrated conditioned media from CHO cellsstably expressing human LOXL2. To assay for amine oxidase activity, 10μL of the concentrated conditioned media is incubated with 2 μL of testcompound in DMSO and 73 μL Assay Buffer (50 mM Borate Buffer, pH8) for 2h at 37° C. After the 2 h incubation, 5 ul of 10 mM 1,5-Diaminopentane(DAP) diluted in Assay Buffer and 10 μl of Amplex Red Mix (8.5 μl AssayBuffer+0.5 μl of 10 mM Amplex Red+1 μl of 500 U/ml HorseradishPeroxidase) are added and the plate mixed and immediately placed on theFlexStaion for fluorescence measurements. Fluorescence is read inkinetic mode every 2 min for 1 hour at excitation=544 and emission=590.The amine oxidase activity is calculated from the slope of the linearportion of the curve.

TABLE 5 Compound Number IC₅₀ 1-1 A 1-2 A 1-3 A 1-4 A 1-5 A 1-6 A 1-7 A1-8 A 1-9 A 1-10 A 1-11 B 1-12 A 1-13 A 1-14 A 1-15 A 1-16 A 1-17 A 1-18A 1-19 A 1-20 A 1-21 A 1-22 A 1-23 A 1-24 A 1-25 A 1-26 A 1-27 A 1-28 A1-29 A 1-30 A 1-31 A 1-32 A 1-33 A 1-34 A 1-35 A 1-36 A 1-37 A 1-38 A1-39 A 1-40 A 1-41 A 1-42 A 1-43 A 1-44 A 1-45 A 2-1 C 2-2 C 2-3 A 2-4 A2-5 B 2-6 B 2-7 B 2-8 A 2-9 B 2-10 A 2-11 A 2-12 A 2-13 A 2-14 A 2-15 A2-16 A 2-17 A 2-18 A 2-19 A 2-20 A 2-21 A 2-22 A 2-23 A 2-24 A 2-25 A2-26 A 2-27 A 2-28 A 2-29 B 2-30 A 2-31 A 2-32 A 2-33 A 2-34 2-35 A 2-36A 2-37 A 2-38 A 2-39 A 2-40 A 2-41 A 2-42 B 2-43 B 3-1 C 3-2 B 3-3 B 4-1C 4-2 B 4-3 B 4-4 A 4-5 A 4-6 C 4-7 A 4-8 A 4-9 A 4-10 C 4-11 A 4-12 C4-13 A 4-14 B A is <0.3 uM; B is 0.3 to 1.0 uM; C is >1.0 uM

Example B-2: LOXL2 Human Blood Amine Oxidase Activity Assay

The amine oxidase activity of human LOXL2 in the context of human wholeblood is measured using an Amplex Red assay. Human, recombinant humanLOXL2 (purchased from Sino Biologicals, Beijing, China) is added tohuman blood collected in heparin vacutainer tubes. Briefly, 0.5-2 μgrecombinant, human LOXL2 (reconstituted in water) and 2 μl test compoundin DMSO is added to 192 μl blood, mixed and incubated at 37° C. for 2 h.After the 2 h incubation, the blood is centrifuged at 2000×g for 15 minat room temperature to isolate the plasma. 50 μl of plasma is removedand mixed with 25 μl of 40 mM DAP (diluted in water) and 25 μl AmplexRed Mix (23.5 μl 50 mM Borate Buffer, pH8+0.5 μl 10 mM Amplex Red+1 μl500 U/ml Horseradish Peroxidase). Samples are mixed and immediatelyplaced on the FlexStaion for fluorescence measurements. Fluorescence isread in kinetic mode every 2 min for 1 hour at excitation=544 andemission=590. The amine oxidase activity is calculated from the slope ofthe linear portion of the curve.

Example B-3: Mouse Oropharyngeal Bleomycin Model of Lung Fibrosis

Lung fibrosis is induced in C57B1/6 male mice by administering bleomycin(0.1-4 U/kg) via oropharyngeal instillation. Mice are either pretreatedwith vehicle or test compound (1 day to 1 hour) orally,intraperitoneally, intravenously or subcutaneously before bleomycininstallation (prophylactic dosing) or 7-14 days post bleomycininstillation (therapeutic dosing). The route and frequency of dosing arebased on previously determined pharmacokinetic properties for the LOXL2inhibitor in mouse. After bleomycin instillation animals are monitoreddaily for weight loss and clinical signs for 14-28 days prior tosacrifice. Animals are euthanized at study termination and weighed andblood (for isolation of plasma) and bronchoalveolar lavage are collectedand frozen for subsequent analyses. Lungs are removed, weighed, theneither inflated and fixed by instillation of 10% formalin and preparedfor histological examination or homogenized in 1 ml PBS for collagendetermination using a hydroxyproline assay. For histologicalexamination, lung slices are stained with Masson's trichrome orPicro-Sirius red to measure cross-linked collagen as an indicator offibrosis and an Ashcroft score of lung fibrotic and inflammatory damagedetermined. In addition, immunohistochemistry of fibrotic proteins suchas a-smooth muscle actin can be recorded. For lung hydroxyprolinecontent, 0.5 ml of the lung homogenate is removed and added to 0.5 ml 12N HCl and the samples heated at 120° C. overnight. After the acidhydrolysis, 25-100 μl of the supernatant is dried down, resuspended in25 μl water and the hydroxyproline content determined by the addition of0.5 ml Chloramine T solution (140 mg Chloramine T in 6.5 ml ddH₂0+1 mln-propanol+2.5 ml 1M sodium acetate) and incubation at room temperaturefor 20 min. After the incubation, 0.5 ml Erlich's solution (1.48 g of4-(dimethylamino(benzaldehyde) in 7 ml n-propanol+2.88 ml 60% perchloricacid and 0.12 ml ddH₂O) is added and incubated at 65° C. for 15 minbefore reading the absorbance at 550 nm. The concentration ofhydroxyproline in each skin biopsy is determined from a hydroxyproline(purchased from Sigma) standard curve.

Example B-4: Mouse Subcutaneous Bleomycin Model of Skin and LungFibrosis

Skin and lung fibrosis is induced in female C57Bl/6 mice byadministering bleomycin via subsutaneous injection to two sites (50 μgbleo/site) on the backs of mice. Animals are anesthetized withisoflurane and bleomycin (100 μl, or PBS control) is injected at thesame site daily for 28 days to induce skin and lung fibrosis. Mice areeither pretreated with vehicle or test compound (1 day to 1 hour)orally, intraperitoneally, intravenously or subcutaneously beforebleomycin injection (prophylactic dosing) or 7-14 days post bleomycininjection (therapeutic dosing). Animals are euthanized at studytermination and weighed and blood (for isolation of plasma) andbronchoalveolar lavage are collected and frozen for subsequent analyses.Lungs are either removed, weighed, then homogenized in PBS fordetermination of collagen content using a hydroxyproline assay orinflated and fixed by instillation of 10% formalin and prepared forhistological examination by trichrome staining or Picrosirius redstaining. Skin biopsies are taken from each injection site using a 6 mmdermal punch biopsy (Acuderm). One punch biopsy is sandwiched in acassette with a sponge, placed in formalin and prepared for histologicalexamination by H&E staining, trichrome staining and/or Picrosirius redstaining. The other punch biopsy is placed in 0.5 ml PBS and mincedusing fine scissors. 500 μl 12 N HCl is then added and the samplesheated at 120° C. overnight. After the acid hydrolysis, 25-100 μl of thesupernatant is dried down, resuspended in 25 μl water and thehydroxyproline content determined by the addition of 0.5 ml Chloramine Tsolution (140 mg Chloramine T in 6.5 ml ddH₂0+1 ml n-propanol+2.5 ml 1Msodium acetate) and incubation at room temperature for 20 min. After theincubation, 0.5 ml Erlich's solution (1.48 g of4-(dimethylamino(benzaldehyde) in 7 ml n-propanol+2.88 ml 60% perchloricacid and 0.12 ml ddH₂O) is added and incubated at 65° C. for 15 minbefore reading the absorbance at 550 nm. The concentration ofhydroxyproline in each skin biopsy is determined from a hydroxyproline(purchased from Sigma) standard curve.

Example B-5: Rat/Mouse CCl₄ Model of Liver Fibrosis

Liver fibrosis is induced in mice (Balb/c or C57Bl/6) by intraperitonealadministration of CCl₄ (0.5-2 ml/kg body weight) diluted in corn oiltwice weekly for 4-8 weeks or by oral administration two-three timesweekly using an escalating dose protocol (Popov et al. 2011Gastroenetrology; 140(5): 1642-1652). Liver fibrosis is induced in ratsby either intraperitoneal administration (1-2.5 ml/kg) or by oraladministration in oil (mineral, olive or corn) twice weekly for 6-12weeks. LOXL2 inhibitors are delivered orally, intraperitoneally,intravenously or subcutaneously 1 day to 1 hour prior to the initialCCl₄ dosing (prophylactic dosing) or 1-4 weeks after the initial CCl₄dosing (therapeutic dosing). At the end of the study, mice aresacrificed by opening the chest cavity under isoflurane, blood is drawnvia cardiac puncture into EDTA vacutainer tubes and the liver isharvested. Part of the liver is fixed in 10% neutral buffered formalinfor subsequent histopathological analysis of inflammation and fibrosisby H&E staining and Picrosirius red staining. The remaining tissue issnap frozen at −80 OC for subsequent hydroxyproline analysis of totalcollagen content

Example B-6: Mouse Mdr2 Knockout Model of Biliary Fibrosis

Liver disease develops in the BALB/c. Mdr2-/−mouse model with bridgingfibrosis/early cirrhosis between 8 and 12 weeks of age (Ikenaga et al.2015 Am J Pathology, 185: 325-334). LOXL2 inhibitors are deliveredorally, intraperitoneally, intravenously or subcutaneously into BALB/c.Mdr2-/−mice once daily for 6 weeks beginning at week 6 after birth. Atthe end of the study, mice are anesthetized with isoflurane (1.5% v/v)via precise vaporizer. After laparotomy, portal pressure is measureddirectly by inserting a high-fidelity pressure catheter into the portalvein and measuring pressure signals for 5 minutes. Serum is collectedfor analysis of liver (ALT, AST, ALP, and bilirubin) and kidney(creatinine) biochemistries. Part of the liver is fixed in 10% neutralbuffered formalin for histopathological analysis of inflammation,necrosis and fibrosis by H&E staining and Picrosirius red staining.Collagen content is determined from a portion of the liver tissue usinghydroxyproline analysis.

Example B-7: Mouse Alport Model of Kidney Fibrosis

Mice with mutations in one of the genes of glomerular basement membranecollagen, Collagen IV-a3/a4/a5, have defects in glomerular function withdevelopment of kidney fibrosis These mice develop renal dysfunction anddie prematurely of renal failure with specific timing dependent on thestrain background upon which the mutation is present. LOXL2 inhibitorsare administered orally to Col4A3 deficient mice on a SV129 backgroundeither prophylactically (ca. weeks 2-3 of age) or therapeutically (ca.weeks 4-6 wks of age). Mice are either sacrificed at a predefined time(7-9 wks of age) or continually dosed until they lose >15% of their bodyweight which precedes death by 1-3 days. If specifically terminated,mice are perfused transcardially with PBS, and one kidney clamped at therenal artery and the other perfused with Dynabeads for magneticisolation of glomeruli. The other kidney is halved and a small sample ofrenal cortex fixed for transmission electron microscopic (TEM) analysisand a second sample of renal cortex used for RNA isolation. The otherhalf of the bisected kidney is embedded in OCT for immunohistochemicalanalysis. RNA from glomeruli and renal cortex is analyzed by real timeRT-PCR for genes of interest including MMP-10, MMP-12, IL6, MCP-1,TGF-b1, CTGF, MMP-2, and MMP-9. Immunohistochemical analysis willinclude staining for collagen 1, CD45, fibronectin, smooth muscle actin,WT-1, and integrin alpha 8/laminin α5. Collagen 1 staining is blindlyanalyzed for fibrosis scoring, and fibronectin staining is blindlyanalyzed for glomerulosclerosis scoring. For all studies albuminuria isassessed weekly and BUN at the time of tissue harvest.

The examples and embodiments described herein are for illustrativepurposes only and various modifications or changes suggested to personsskilled in the art are to be included within the spirit and purview ofthis application and scope of the appended claims.

What is claimed is:
 1. A compound of Formula (VI), or a pharmaceuticallyacceptable salt, or solvate thereof:

wherein, each R¹ is independently H, D, or F; R^(A) is H, D, halogen,—CN, —OR⁵, —N(R⁵)₂, or substituted or unsubstituted phenyl; L¹ isabsent, —O—, —S—, —S(═O)—, —S(═O)₂—, or —NR²—; R² is H, C₁-C₆alkyl,C₁-C₆fluoroalkyl, or C₁-C₆deuteroalkyl; each R³ is independently H, D,halogen, —CN, C₁-C₆alkyl, C₁-C₆fluoroalkyl, or C₁-C₆deuteroalkyl; m is0, 1, or 2; each R⁴ is independently selected from C₁-C₆alkyl,C₁-C₆fluoroalkyl, C₁-C₆deuteroalkyl, C₁-C₆heteroalkyl, substituted orunsubstituted C₃-C₁₀cycloalkyl, and substituted or unsubstituted aryl;each R⁵ is independently selected from H, C₁-C₆alkyl, C₁-C₆fluoroalkyl,C₁-C₆deuteroalkyl, C₁-C₆heteroalkyl, substituted or unsubstitutedC₃-C₁₀cycloalkyl, substituted or unsubstituted aryl,—C₁-C₄alkylene-(substituted or unsubstituted C₃-C₈cycloalkyl),substituted or unsubstituted aryl, and —C₁-C₄alkylene-(substituted orunsubstituted aryl); Ring A is phenyl; or Ring A is bicyclicC₉-C₁₀carbocycle; R⁶ is H, C₁-C₆alkyl, C₁-C₆fluoroalkyl, orC₁-C₆deuteroalkyl; Q is substituted or unsubstituted C₁-C₆alkyl,substituted or unsubstituted C₁-C₆fluoroalkyl, substituted orunsubstituted C₁-C₆heteroalkyl, substituted or unsubstitutedC₃-C₈cycloalkyl, —C₁-C₄alkylene-(substituted or unsubstitutedC₃-C₈cycloalkyl), substituted or unsubstituted aryl,—C₁-C₄alkylene-(substituted or unsubstituted aryl), substituted orunsubstituted heteroaryl, or —C₁-C₄alkylene-(substituted orunsubstituted heteroaryl); wherein if Q is substituted then Q issubstituted with one or more R⁸; or Q and R⁶ are taken together with theN atom to which they are attached to form a ring B, wherein ring B is asubstituted or unsubstituted pyrrolidinyl, wherein if ring B issubstituted then ring B is substituted with 1-3 R⁸; each R⁸ isindependently D, halogen, CN, —OR⁵, —SR⁵, —S(═O)R⁴, —S(═O)₂R⁴,—S(═O)₂N(R⁵)₂, NR⁵S(═O)₂R⁴, C(═O)R⁴, OC(═O)R⁴, CO₂R⁵, OCO₂R⁴, N(R⁴)₂,OC(═O)N(R⁵)₂, —NHC(═O)R⁴, —NHC(═O)OR⁴, C₁-C₆alkyl, C₁-C₆fluoroalkyl,C₁-C₆deuteroalkyl, C₁-C₆heteroalkyl, substituted or unsubstitutedC₃-C₁₀cycloalkyl, substituted or unsubstituted aryl, or substituted orunsubstituted heteroaryl; or two R⁸ groups attached to the same carbonatom are taken together with the carbon atom to which they are attachedto form a substituted or unsubstituted carbocycle; wherein anysubstituted group of R^(A), R³, R⁴, R⁵, and R⁸ is substituted with oneor more additional groups individually and independently selected fromhalogen, —CN, —NH₂, —NH(CH₃), —N(CH₃)₂, —OH, —CO₂H, —CO₂(C₁-C₄alkyl),—C(═O)NH₂, —C(═O)NH(C₁-C₄alkyl), —C(═O)N(C₁-C₄alkyl)₂, —S(═O)₂NH₂,—S(═O)₂NH(C₁-C₄alkyl), —S(═O)₂N(C₁-C₄alkyl)₂, C₁-C₄alkyl,C₃-C₆cycloalkyl, C₁-C₄fluoroalkyl, C₁-C₄heteroalkyl, C₁-C₄alkoxy,C₁-C₄fluoroalkoxy, —SC₁-C₄alkyl, —S(═O)C₁-C₄alkyl, and—S(═O)₂C₁-C₄alkyl.
 2. The compound of claim 1, or a pharmaceuticallyacceptable salt, or solvate thereof, wherein: each R¹ is H.
 3. Thecompound of claim 2, or a pharmaceutically acceptable salt, or solvatethereof, wherein: Ring A is phenyl; or Ring A is bicyclicC₉-C₁₀carbocycle that is naphthyl, indanyl, indenyl, ortetrahyodronaphthyl.
 4. The compound of claim 3, or a pharmaceuticallyacceptable salt, or solvate thereof, wherein: Ring A is


5. The compound of claim 3, or a pharmaceutically acceptable salt, orsolvate thereof, wherein: Q is substituted or unsubstitutedC₃-C₆cycloalkyl, —C₁-C₂alkylene-(substituted or unsubstitutedC₃-C₆cycloalkyl), substituted or unsubstituted phenyl,—C₁-C₂alkylene-(substituted or unsubstituted phenyl), substituted orunsubstituted heteroaryl, or —C₁-C₂alkylene-(substituted orunsubstituted heteroaryl); wherein if Q is substituted then Q issubstituted with one or more R⁸; or Q and R⁶ are taken together with theN atom to which they are attached to form a ring B, wherein ring B is asubstituted or unsubstituted pyrrolidinyl, wherein if ring B issubstituted then ring B is substituted with 1-3 R⁸.
 6. The compound ofclaim 5, or a pharmaceutically acceptable salt, or solvate thereof,wherein: Q and R⁶ are taken together with the N atom to which they areattached to form a ring B, wherein ring B is a substituted orunsubstituted pyrrolidinyl, wherein if ring B is substituted then ring Bis substituted with 1-3 R⁸.
 7. The compound of claim 5, wherein thecompound has the structure of Formula (VII), or a pharmaceuticallyacceptable salt, or solvate thereof:

wherein, ring B is a substituted or unsubstituted pyrrolidinyl, whereinif ring B is substituted then ring B is substituted with 1-3 R⁸; and nis 0, 1, 2, or
 3. 8. The compound of claim 1, wherein the compound hasthe structure of Formula (XII), or a pharmaceutically acceptable salt,or solvate thereof:


9. The compound of claim 1, wherein the compound has the structure ofFormula (XIII), or a pharmaceutically acceptable salt, or solvatethereof:

wherein, L₁ is —O—.
 10. A compound that is:4-(4-(Aminomethyl)pyridin-2-yl)-N-(2-methoxyethyl)benzamide;Racemic-(4-(4-(aminomethyl)pyridin-2-yl)phenyl)(3-hydroxy-3-(trifluoromethyl)pyrrolidin-1-yl)methanone;4-(4-(Aminomethyl)pyridin-2-yl)-N-phenylbenzamide;4-(4-(Aminomethyl)pyridin-2-yl)-N-benzylbenzamide;3-(4-(Aminomethyl)pyridin-2-yl)-N-(2-methoxyethyl)benzamide;Racemic-(3-(4-(aminomethyl)pyridin-2-yl)phenyl)(3-hydroxy-3-(trifluoromethyl)pyrrolidin-1-yl)methanone;3-(4-(Aminomethyl)pyridin-2-yl)-N-phenylbenzamide;3-(4-(Aminomethyl)pyridin-2-yl)-N-benzylbenzamide;3-(4-(Aminomethyl)pyridin-2-yl)-N-(5-chloro-2-methylphenyl)benzamide;3-(4-(Aminomethyl)pyridin-2-yl)-N-(6-chloro-1H-indol-4-yl)benzamide;4-((4-(Aminomethyl)pyridin-2-yl)oxy)-N-(2-methoxyethyl)benzamide;Racemic-4-((4-(aminomethyl)pyridin-2-yl)oxy)phenyl)(3-hydroxy-3-(trifluoromethyl)pyrrolidin-1-yl)methanone;4-((4-(Aminomethyl)pyridin-2-yl)oxy)-N-phenylbenzamide;4-((4-(Aminomethyl)pyridin-2-yl)oxy)-N-benzylbenzamide;3-((4-(Aminomethyl)pyridin-2-yl)oxy)-N-(2-methoxyethyl)benzamide;Racemic-(3-((4-(aminomethyl)pyridin-2-yl)oxy)phenyl)(3-hydroxy-3-(trifluoromethyl)pyrrolidin-1-yl)methanone;3-((4-(Aminomethyl)pyridin-2-yl)oxy)-N-phenylbenzamide;3-((4-(Aminomethyl)pyridin-2-yl)oxy)-N-benzylbenzamide;3-((4-(Aminomethyl)pyridin-2-yl)oxy)-N-(3-methoxyphenyl)benzamide;3-((4-(Aminomethyl)pyridin-2-yl)oxy)-N-(4-methoxyphenyl)benzamide;3-((4-(Aminomethyl)pyridin-2-yl)oxy)-N-(3-(trifluoromethyl)phenyl)benzamide;3-((4-(Aminomethyl)pyridin-2-yl)oxy)-N-(4-(trifluoromethyl)phenyl)benzamide;3-((4-(Aminomethyl)pyridin-2-yl)oxy)-N-(4-fluorophenyl)benzamide;3-((4-(Aminomethyl)pyridin-2-yl)oxy)-N-(2,4-difluorophenyl)benzamide;3-((4-(Aminomethyl)pyridin-2-yl)oxy)-N-(4-bromophenyl)benzamide; Methyl4-(3-((4-(aminomethyl)pyridin-2-yl)oxy)benzamido)benzoate; Ethyl3-(3-((4-(aminomethyl)pyridin-2-yl)oxy)benzamido)benzoate;3-(3-((4-(Aminomethyl)pyridin-2-yl)oxy)benzamido)benzoic acid;4-(3-((4-(Aminomethyl)pyridin-2-yl)oxy)benzamido)benzoic acid;3-((4-(Aminomethyl)pyridin-2-yl)oxy)-N-(2,4-difluorobenzyl)benzamide;3-((4-(Aminomethyl)pyridin-2-yl)oxy)-N-(4-(trifluoromethyl)benzyl)benzamide;3-((4-(Aminomethyl)pyridin-2-yl)oxy)-N-(4-bromobenzyl)benzamide; Methyl4-((3-((4-(aminomethyl)pyridin-2-yl)oxy)benzamido)methyl)benzoate;4-((3-((4-(Aminomethyl)pyridin-2-yl)oxy)benzamido)methyl)benzoic acid;3-((3-((4-(Aminomethyl)pyridin-2-yl)oxy)benzamido)methyl)benzoic acid;(R)-3-((4-(Aminomethyl)pyridin-2-yl)oxy)-N-(2-hydroxy-1-phenylethyl)benzamide;3-((4-(Aminomethyl)pyridin-2-yl)oxy)-N-(3-fluoro-4-(1H-imidazol-1-yl)benzyl)benzamide;3-((4-(Aminomethyl)pyridin-2-yl)oxy)-N-(4-(4-ethylpiperazin-1-yl)benzyl)benzamide;3-((4-(Aminomethyl)pyridin-2-yl)oxy)-N-(3-carbamimidoylbenzyl)benzamide;3-((4-(Aminomethyl)pyridin-2-yl)oxy)-N-phenethylbenzamide;(3-((4-(Aminomethyl)pyridin-2-yl)oxy)phenyl)(3,4-dihydroisoquinolin-2(1H)-yl)methanone;3-((4-(Aminomethyl)pyridin-2-yl)oxy)-N-(benzo[b]thiophen-2-ylmethyl)benzamide;3-((4-(Aminomethyl)pyridin-2-yl)oxy)-N-(pyrazin-2-ylmethyl)benzamide;3-((4-(Aminomethyl)pyridin-2-yl)oxy)-N-tridecylbenzamide; or3-(((4-(Aminomethyl)pyridin-2-yl)oxy)methyl)-N-phenylbenzamide; or apharmaceutically acceptable salt, or solvate thereof.
 11. Apharmaceutical composition comprising a compound, or a pharmaceuticallyacceptable salt, or solvate thereof, of claim 1, and at least onepharmaceutically acceptable excipient.